Treatment of non-alcoholic fatty liver disease

ABSTRACT

According to some embodiments, a method of treating a subject having diabetes or symptoms associated with diabetes is provided. The method includes delivering a neuromodulation catheter within a vessel (e.g., hepatic artery) having surrounding nerves that innervate the liver (e.g., sympathetic nerves of the hepatic plexus). The method may also include modulating (e.g., disrupting, ablating, stimulating) the nerves by mechanical compression, energy delivery, or fluid delivery.

RELATED APPLICATIONS

The present application is a continuation of U.S. application Ser. No.13/789,509, filed Mar. 7, 2013, which is a continuation of InternationalApplication No. PCT/US2012/068630, filed Dec. 7, 2012, which claimspriority to U.S. Provisional Application No. 61/568,843, filed Dec. 9,2011, the entirety of each of which is hereby incorporated by referenceherein.

FIELD

The disclosure relates generally to therapeutic neuromodulation and morespecifically to embodiments of devices, systems and methods fortherapeutically effecting neuromodulation of targeted nerve fibers of,for example, the hepatic system, to treat metabolic diseases orconditions, such as diabetes mellitus.

BACKGROUND

Chronic hyperglycemia is one of the defining characteristics of diabetesmellitus. Hyperglycemia is a condition in which there is an elevatedblood glucose concentration. An elevated blood glucose concentration mayresult from impaired insulin secretion from the pancreas and also, oralternatively, from cells failing to respond to insulin normally.Excessive glucose release from the kidneys and the liver is asignificant contributor to fasting hyperglycemia. The liver isresponsible for approximately 90% of the excessive glucose production.

Type 1 diabetes mellitus results from autoimmune destruction of thepancreatic beta cells leading to inadequate insulin production. Type 2diabetes mellitus is a more complex, chronic metabolic disorder thatdevelops due to a combination of insufficient insulin production as wellas cellular resistance to the action of insulin. Insulin promotesglucose uptake into a variety of tissues and also decreases productionof glucose by the liver and kidneys; insulin resistance results inreduced peripheral glucose uptake and increased endogenous glucoseoutput, both of which drive blood the glucose concentration above normallevels.

Current estimates are that approximately 26 million people in the UnitedStates (over 8% of the population) have some form of diabetes mellitus.Treatments, such as medications, diet, and exercise, seek to controlblood glucose levels, which require a patient to closely monitor his orher blood glucose levels. Additionally, patients with type 1 diabetesmellitus, and many patients with type 2 diabetes mellitus, are requiredto take insulin every day. Insulin is not available in a pill form,however, but must be injected under the skin. Because treatment fordiabetes mellitus is self-managed by the patient on a day-to-day basis,compliance or adherence with treatments can be problematic.

SUMMARY

Several embodiments described herein relate generally to devices,systems and methods for therapeutically effecting neuromodulation oftargeted nerve fibers to treat various medical conditions, disorders anddiseases. In some embodiments, neuromodulation of targeted nerve fibersis used to treat, or reduce the risk of occurrence of symptomsassociated with, a variety of metabolic diseases. For example,neuromodulation of targeted nerve fibers can treat, or reduce the riskof occurrence of symptoms associated with, diabetes (e.g., diabetesmellitus) or other diabetes-related diseases. The methods describedherein can advantageously treat diabetes without requiring daily insulininjection or constant monitoring of blood glucose levels. The treatmentprovided by the devices, systems and methods described herein can bepermanent or at least semi-permanent (e.g., lasting for several weeks,months or years), thereby reducing the need for continued or periodictreatment. Embodiments of the devices described herein can be temporaryor implantable.

In some embodiments, neuromodulation of targeted nerve fibers asdescribed herein can be used for the treatment of insulin resistance,genetic metabolic syndromes, ventricular tachycardia, atrialfibrillation or flutter, arrhythmia, inflammatory diseases,hypertension, obesity, hyperglycemia, hyperlipidemia, eating disorders,and/or endocrine diseases. In some embodiments, neuromodulation oftargeted nerve fibers treats any combination of diabetes, insulinresistance, or other metabolic diseases. In some embodiments, temporaryor implantable neuromodulators may be used to regulate satiety andappetite. In several embodiments, modulation of nervous tissue thatinnervates (afferently or efferently) the liver is used to treathemochromatosis, Wilson's disease, non-alcoholic steatohepatitis (NASH),non-alcoholic fatty liver disease (NAFLD), and/or other conditionsaffecting the liver and/or liver metabolism.

In some embodiments, sympathetic nerve fibers associated with the liverare selectively disrupted (e.g., ablated, denervated, disabled, severed,blocked, desensitized, removed) to decrease hepatic glucose productionand/or increase hepatic glucose uptake, thereby aiding in the treatmentof, or reduction in the risk of, diabetes and/or related diseases ordisorders. The disruption can be permanent or temporary (e.g., for amatter of several days, weeks or months). In some embodiments,sympathetic nerve fibers in the hepatic plexus are selectivelydisrupted. In some embodiments, sympathetic nerve fibers surrounding thecommon hepatic artery proximal to the proper hepatic artery, sympatheticnerve fibers surrounding the proper hepatic artery, sympathetic nervefibers in the celiac ganglion adjacent the celiac artery, othersympathetic nerve fibers that innervate or surround the liver,sympathetic nerve fibers that innervate the pancreas, sympathetic nervefibers that innervate fat tissue (e.g., visceral fat), sympathetic nervefibers that innervate the adrenal glands, sympathetic nerve fibers thatinnervate the small intestine (e.g., duodenum), sympathetic nerve fibersthat innervate the stomach, sympathetic nerve fibers that innervatebrown adipose tissue, sympathetic nerve fibers that innervate skeletalmuscle, and/or sympathetic nerve fibers that innervate the kidneys areselectively disrupted or modulated to facilitate treatment or reductionof symptoms associated with diabetes (e.g., diabetes mellitus) or othermetabolic diseases or disorders. In some embodiments, the methods,devices and systems described herein are used to therapeuticallymodulate autonomic nerves associated with any diabetes-relevant organsor tissues.

In accordance with several embodiments, any nerves containing autonomicfibers are modulated, including, but not limited to, the saphenousnerve, femoral nerves, lumbar nerves, median nerves, ulnar nerves, vagusnerves, and radial nerves. Nerves surrounding arteries or veins otherthan the hepatic artery may be modulated such as, but not limited to,nerves surrounding the superior mesenteric artery, the inferiormesenteric artery, the femoral artery, the pelvic arteries, the portalvein, pulmonary arteries, pulmonary veins, abdominal aorta, vena cavas,splenic arteries, gastric arteries, the internal carotid artery, theinternal jugular vein, the vertebral artery, renal arteries, and renalveins.

In accordance with several embodiments, a therapeutic neuromodulationsystem is used to selectively disrupt sympathetic nerve fibers. Theneuromodulation system can comprise an ablation catheter system and/or adelivery catheter system. An ablation catheter system may useradiofrequency (RF) energy to ablate sympathetic nerve fibers to causeneuromodulation or disruption of sympathetic communication. In someembodiments, an ablation catheter system uses ultrasonic energy toablate sympathetic nerve fibers. In some embodiments, an ablationcatheter system uses ultrasound (e.g., high-intensity focused ultrasoundor low-intensity focused ultrasound) energy to selectively ablatesympathetic nerve fibers. In other embodiments, an ablation cathetersystem uses electroporation to modulate sympathetic nerve fibers. Anablation catheter, as used herein, shall not be limited to causingablation, but also includes devices that facilitate the modulation ofnerves (e.g., partial or reversible ablation, blocking without ablation,stimulation). In some embodiments, a delivery catheter system deliversdrugs or chemical agents to nerve fibers to modulate the nerve fibers(e.g., via chemoablation). Chemical agents used with chemoablation (orsome other form of chemically-mediated neuromodulation) may, forexample, include phenol, alcohol, or any other chemical agents thatcause chemoablation of nerve fibers. In some embodiments, cryotherapy isused. For example, an ablation catheter system is provided that usescryoablation to selectively modulate (e.g., ablate) sympathetic nervefibers. In other embodiments, a delivery catheter system is used withbrachytherapy to modulate the nerve fibers. The catheter systems mayfurther utilize any combination of RF energy, ultrasonic energy, focusedultrasound (e.g., HIFU, LIFU) energy, ionizing energy (such as X-ray,proton beam, gamma rays, electron beams, and alpha rays),electroporation, drug delivery, chemoablation, cryoablation,brachytherapy, or any other modality to cause disruption orneuromodulation (e.g., ablation, denervation, stimulation) of autonomic(e.g., sympathetic or parasympathetic) nerve fibers.

In some embodiments, a minimally invasive surgical technique is used todeliver the therapeutic neuromodulation system. For example, a cathetersystem for the disruption or neuromodulation of sympathetic nerve fiberscan be delivered intra-arterially (e.g., via a femoral artery, brachialartery, radial artery). In some embodiments, an ablation catheter systemis advanced to the proper hepatic artery to ablate (completely orpartially) sympathetic nerve fibers in the hepatic plexus. In otherembodiments, the ablation catheter system is advanced to the commonhepatic artery to ablate sympathetic nerve fibers surrounding the commonhepatic artery. In some embodiments, the ablation catheter system isadvanced to the celiac artery to ablate sympathetic nerve fibers in theceliac ganglion or celiac plexus. An ablation or delivery cathetersystem can be advanced within other arteries (e.g., left hepatic artery,right hepatic artery, gastroduodenal artery, gastric arteries, splenicartery, renal arteries, etc.) in order to disrupt targeted sympatheticnerve fibers associated with the liver or other organs or tissue (suchas the pancreas, fat tissue (e.g., visceral fat of the liver), theadrenal glands, the stomach, the small intestine, bile ducts, brownadipose tissue, skeletal muscle), at least some of which may beclinically relevant to diabetes.

In some embodiments, a therapeutic neuromodulation or disruption systemis delivered intravascularly through the venous system. For example, thetherapeutic neuromodulation system may be delivered either through theportal vein or through the inferior vena cava. In some embodiments, theneuromodulation system is delivered percutaneously to the biliary treeto modulate or disrupt sympathetic nerve fibers.

In other embodiments, the neuromodulation system is deliveredtransluminally or laparoscopically to modulate or disrupt sympatheticnerve fibers. For example, the neuromodulation system may be deliveredtransluminally either through the stomach, or through the duodenum.

In some embodiments, minimally invasive surgical delivery of theneuromodulation system is accomplished in conjunction with imageguidance techniques. For example, a visualization device such as afiberoptic scope can be used to provide image guidance during minimallyinvasive surgical delivery of the neuromodulation system. In someembodiments, fluoroscopic, computerized tomography (CT), radiographic,optical coherence tomography (OCT), intravascular ultrasound (IVUS),Doppler, thermography, and/or magnetic resonance (MR) imaging is used inconjunction with minimally invasive surgical delivery of theneuromodulation system. In some embodiments, radiopaque markers arelocated at a distal end of the neuromodulation system to aid in deliveryand alignment of the neuromodulation system.

In some embodiments, an open surgical procedure is used to access thenerve fibers to be modulated. In some embodiments, any of the modalitiesdescribed herein, including, but not limited to, RF energy, ultrasonicenergy, HIFU, thermal energy, light energy, electrical energy other thanRF energy, drug delivery, chemoablation, cryoablation, steam orhot-water, ionizing energy (such as X-ray, proton beam, gamma rays,electron beams, and alpha rays) or any other modality are used inconjunction with an open surgical procedure to modulate or disruptsympathetic nerve fibers. In other embodiments, nerve fibers aresurgically cut (e.g., transected) to disrupt conduction of nervesignals.

In some embodiments, a non-invasive (e.g., transcutaneous) procedure isused to modulate or disrupt sympathetic nerve fibers. In someembodiments, any of the modalities described herein, including, but notlimited, to RF energy, ultrasonic energy, HIFU energy, radiationtherapy, light energy, infrared energy, thermal energy, steam, hotwater, magnetic fields, ionizing energy, other forms of electrical orelectromagnetic energy or any other modality are used in conjunctionwith a non-invasive procedure to modulate or disrupt sympathetic nervefibers.

In accordance with some embodiments, the neuromodulation system is usedto modulate or disrupt sympathetic nerve fibers at one or more locationsor target sites. For example, an ablation catheter system may performablation in a circumferential or radial pattern, and/or the ablationcatheter system may perform ablation at a plurality of points linearlyspaced apart along a vessel length. In other embodiments, an ablationcatheter system performs ablation at one or more locations in any otherpattern capable of causing disruption in the communication pathway ofsympathetic nerve fibers (e.g., spiral patterns, zig-zag patterns,multiple linear patterns, etc.). The pattern can be continuous ornon-continuous (e.g., intermittent). The ablation may be targeted atcertain portions of the circumference of the vessels (e.g., half orportions less than half of the circumference).

In accordance with embodiments of the invention disclosed herein,therapeutic neuromodulation to treat various medical disorders anddiseases includes neural stimulation of targeted nerve fibers. Forexample, autonomic nerve fibers (e.g., sympathetic nerve fibers,parasympathetic nerve fibers) may be stimulated to treat, or reduce therisk of occurrence of, diabetes (e.g., diabetes mellitus) or otherconditions, diseases and disorders.

In some embodiments, parasympathetic nerve fibers that innervate theliver are stimulated. In some embodiments, parasympathetic nerve fibersthat innervate the pancreas, fat tissue (e.g., visceral fat of theliver), the adrenal glands, the stomach, the kidneys, brown adiposetissue, skeletal muscle, and/or the small intestine (e.g., duodenum) arestimulated. In accordance with some embodiments, any combination ofparasympathetic nerve fibers innervating the liver, the pancreas, fattissue, the adrenal glands, the stomach, the kidneys, brown adiposetissue, skeletal muscle, and the small intestine are stimulated totreat, or alleviate or reduce the risk of occurrence of the symptomsassociated with, diabetes (e.g., diabetes mellitus) or other conditions,diseases, or disorders. In some embodiments, the organs or tissue arestimulated directly either internally or externally.

In some embodiments, a neurostimulator is used to stimulate sympatheticor parasympathetic nerve fibers. In some embodiments, theneurostimulator is implantable. In accordance with some embodiments, theimplantable neurostimulator electrically stimulates parasympatheticnerve fibers. In some embodiments, the implantable neurostimulatorchemically stimulates parasympathetic nerve fibers. In still otherembodiments, the implantable neurostimulator uses any combination ofelectrical stimulation, chemical stimulation, or any other methodcapable of stimulating parasympathetic nerve fibers.

In other embodiments, non-invasive neurostimulation is used to effectstimulation of parasympathetic nerve fibers. For example, transcutaneouselectrical stimulation may be used to stimulate parasympathetic nervefibers. Other energy modalities can also be used to affect non-invasiveneurostimulation of parasympathetic nerve fibers (e.g., light energy,ultrasound energy).

In some embodiments, neuromodulation of targeted autonomic nerve fiberstreats diabetes (e.g., diabetes mellitus) and related conditions bydecreasing systemic glucose. For example, therapeutic neuromodulation oftargeted nerve fibers can decrease systemic glucose by decreasinghepatic glucose production. In some embodiments, hepatic glucoseproduction is decreased by disruption (e.g., ablation) of sympatheticnerve fibers. In other embodiments, hepatic glucose production isdecreased by stimulation of parasympathetic nerve fibers.

In some embodiments, therapeutic neuromodulation of targeted nervefibers decreases systemic glucose by increasing hepatic glucose uptake.In some embodiments, hepatic glucose uptake is increased by disruption(e.g., ablation) of sympathetic nerve fibers. In other embodiments,hepatic glucose uptake is increased by stimulation of parasympatheticnerve fibers. In some embodiments, triglyceride or cholesterol levelsare reduced by the therapeutic neuromodulation.

In some embodiments, disruption or modulation of the sympathetic nervefibers of the hepatic plexus has no effect on the parasympathetic nervefibers surrounding the liver. In some embodiments, disruption ormodulation (e.g., ablation or denervation) of the sympathetic nervefibers of the hepatic plexus causes a reduction of very low-densitylipoprotein (VLDL) levels, thereby resulting in a beneficial effect onlipid profile. In several embodiments, the invention comprisesneuromodulation therapy to affect sympathetic drive and/or triglycerideor cholesterol levels, including high-density lipoprotein (HDL) levels,low-density lipoprotein (LDL) levels, and/or very-low-densitylipoprotein (VLDL) levels. In some embodiments, denervation or ablationof sympathetic nerves reduces triglyceride levels, cholesterol levelsand/or central sympathetic drive.

In other embodiments, therapeutic neuromodulation of targeted nervefibers (e.g., hepatic denervation) decreases systemic glucose byincreasing insulin secretion. In some embodiments, insulin secretion isincreased by disruption (e.g., ablation) of sympathetic nerve fibers(e.g., surrounding branches of the hepatic artery). In otherembodiments, insulin secretion is increased by stimulation ofparasympathetic nerve fibers. In some embodiments, sympathetic nervefibers surrounding the pancreas may be modulated to decrease glucagonlevels and increase insulin levels. In some embodiments, sympatheticnerve fibers surrounding the adrenal glands are modulated to affectadrenaline or noradrenaline levels. Fatty tissue (e.g., visceral fat) ofthe liver may be targeted to affect glycerol or free fatty acid levels.

In accordance with several embodiments of the invention, a method ofdecreasing blood glucose levels within a subject is provided. The methodcomprises forming an incision in a groin of a subject to access afemoral artery and inserting a neuromodulation catheter into theincision. In some embodiments, the method comprises advancing theneuromodulation catheter from the femoral artery through an arterialsystem to a proper hepatic artery and causing a therapeuticallyeffective amount of energy to thermally inhibit neural communicationalong a sympathetic nerve in a hepatic plexus surrounding the properhepatic artery to be delivered intravascularly by the ablation catheterto the inner wall of the proper hepatic artery, thereby decreasing bloodglucose levels within the subject. Other incision or access points maybe used as desired or required.

In some embodiments, the neuromodulation catheter is a radiofrequency(RF) ablation catheter comprising one or more electrodes. In someembodiments, the neuromodulation catheter is a high-intensity focusedultrasound ablation catheter. In some embodiments, the neuromodulationcatheter is a cryoablation catheter. The method can further comprisestimulating one or more parasympathetic nerves associated with the liverto decrease hepatic glucose production or increase glucose uptake.

In accordance with several embodiments, a method of treating a subjecthaving diabetes or symptoms associated with diabetes is provided. Themethod can comprise delivering an RF ablation catheter to a vicinity ofa hepatic plexus of a subject and disrupting neural communication alonga sympathetic nerve of the hepatic plexus by causing RF energy to beemitted from one or more electrodes of the RF ablation catheter. In someembodiments, the RF ablation catheter is delivered intravascularlythrough a femoral artery to a location within the proper hepatic artery.In some embodiments, the RF energy is delivered extravascularly by theRF ablation catheter.

In some embodiments, disrupting neural communication comprisespermanently disabling neural communication along the sympathetic nerveof the hepatic plexus. In some embodiments, disrupting neuralcommunication comprises temporarily inhibiting or reducing neuralcommunication along the sympathetic nerve of the hepatic plexus. In someembodiments, disrupting neural communication along a sympathetic nerveof the hepatic plexus comprises disrupting neural communication along aplurality of sympathetic nerves of the hepatic plexus.

The method can further comprise positioning the RF ablation catheter inthe vicinity of the celiac plexus of the subject and disrupting neuralcommunication along a sympathetic nerve of the celiac plexus by causingRF energy to be emitted from one or more electrodes of the RF ablationcatheter. In some embodiments, the method comprises positioning the RFablation catheter in the vicinity of sympathetic nerve fibers thatinnervate the pancreas and disrupting neural communication along thesympathetic nerve fibers by causing RF energy to be emitted from one ormore electrodes of the RF ablation catheter, positioning the RF ablationcatheter in the vicinity of sympathetic nerve fibers that innervate thestomach and disrupting neural communication along the sympathetic nervefibers by causing RF energy to be emitted from one or more electrodes ofthe RF ablation catheter, and/or positioning the RF ablation catheter inthe vicinity of sympathetic nerve fibers that innervate the duodenum anddisrupting neural communication along the sympathetic nerve fibers bycausing RF energy to be emitted from one or more electrodes of the RFablation catheter. In some embodiments, drugs or therapeutic agents canbe delivered to the liver or surrounding organs or tissues.

In accordance with several embodiments, a method of decreasing bloodglucose levels within a subject is provided. The method comprisesinserting an RF ablation catheter into vasculature of the subject andadvancing the RF ablation catheter to a location of a branch of ahepatic artery (e.g., the proper hepatic artery or the common hepaticartery). In one embodiment, the method comprises causing atherapeutically effective amount of RF energy to thermally inhibitneural communication within sympathetic nerves of a hepatic plexussurrounding the proper hepatic artery to be delivered intravascularly bythe ablation catheter to the inner wall of the proper hepatic artery,thereby decreasing blood glucose levels within the subject.

In one embodiment, the therapeutically effective amount of RF energy atthe location of the inner vessel wall of the target vessel or at thelocation of the target nerves is in the range of between about 100 J andabout 1 kJ (e.g., between about 100 J and about 500 J, between about 250J and about 750 J, between about 500 J and 1 kJ, or overlapping rangesthereof). In one embodiment, the therapeutically effective amount of RFenergy has a power between about 0.1 W and about 10 W (e.g., betweenabout 0.5 W and about 5 W, between about 3 W and about 8 W, betweenabout 2 W and about 6 W, between about 5 W and about 10 W, oroverlapping ranges thereof).

In one embodiment, the RF ablation catheter comprises at least oneablation electrode. The RF ablation catheter may be configured to causethe at least one ablation electrode to contact the inner wall of thehepatic artery branch and maintain contact against the inner wall withsufficient contact pressure while the RF energy is being delivered. Inone embodiment, the RF ablation catheter comprises a balloon catheterconfigured to maintain sufficient contact pressure of the at least oneelectrode against the inner wall of the hepatic artery branch. In oneembodiment, the RF ablation catheter comprises a steerable distal tipconfigured to maintain sufficient contact pressure of the at least oneelectrode against the inner wall of the hepatic artery branch. Invarious embodiments, the sufficient contact pressure may range fromabout 0.1 g/mm² to about 100 g/mm² (e.g., between about 0.1 g/mm² andabout 10 g/mm²). In some embodiments, the RF ablation catheter comprisesat least one anchoring member configured to maintain contact of the atleast one electrode against the inner wall of the hepatic artery branch.

In accordance with several embodiments, a method of treating a subjecthaving diabetes or symptoms associated with diabetes is provided. In oneembodiment, the method comprises delivering an RF ablation catheter to avicinity of a hepatic plexus within a hepatic artery branch (e.g.,proper hepatic artery, common hepatic artery or adjacent or within abifurcation between the two). In one embodiment, the RF ablationcatheter comprises at least one electrode. The method may comprisepositioning the at least one electrode in contact with an inner wall ofthe hepatic artery branch. In one embodiment, the method comprisesdisrupting neural communication of sympathetic nerves of the hepaticplexus surrounding the hepatic artery branch by applying an electricsignal to the at least one electrode, thereby causing thermal energy tobe delivered by the at least one electrode to heat the inner wall of thehepatic artery branch. Non-ablative heating, ablative heating, orcombinations thereof, are used in several embodiments.

In one embodiment, disrupting neural communication comprises permanentlydisabling neural communication of sympathetic nerves of the hepaticplexus. In one embodiment, disrupting neural communication comprisestemporarily inhibiting or reducing neural communication alongsympathetic nerves of the hepatic plexus. In some embodiments, themethod comprises positioning the RF ablation catheter in the vicinity ofthe celiac plexus of the subject and disrupting neural communicationalong sympathetic nerves of the celiac plexus, positioning the RFablation catheter in the vicinity of sympathetic nerve fibers thatinnervate the pancreas and disrupting neural communication along thesympathetic nerve fibers, positioning the RF ablation catheter in thevicinity of sympathetic nerve fibers that innervate the stomach anddisrupting neural communication along the sympathetic nerve fibers,and/or positioning the RF ablation catheter in the vicinity ofsympathetic nerve fibers that innervate the duodenum and disruptingneural communication along the sympathetic nerve fibers by causing RFenergy to be emitted from the at least one electrode of the RF ablationcatheter. In several embodiments, a feedback mechanism is provided tofacilitate confirmation of neuromodulation and to allow for adjustmentof treatment in real time.

In accordance with several embodiments, a method of treating a subjecthaving diabetes or symptoms associated with diabetes is provided. In oneembodiment, the method comprises delivering a neuromodulation catheterwithin a hepatic artery to a vicinity of a hepatic plexus of a subjectand modulating nerves of the hepatic plexus by causing RF energy to beemitted from one or more electrodes of the RF ablation catheter. In oneembodiment, the step of modulating the nerves of the hepatic plexuscomprises denervating sympathetic nerves of the hepatic plexus and/orstimulating parasympathetic nerves of the hepatic plexus. In oneembodiment, the sympathetic denervation and the parasympatheticstimulation are performed simultaneously. In one embodiment, thesympathetic denervation and the parasympathetic stimulation areperformed sequentially. In one embodiment, sympathetic nerves aremodulated without modulating parasympathetic nerves surrounding the samevessel or tissue.

In accordance with several embodiments, an apparatus configured forhepatic neuromodulation is provided. In one embodiment, the apparatuscomprises a balloon catheter configured for intravascular placementwithin a hepatic artery branch. In one embodiment, the balloon cathetercomprises at least one expandable balloon and a bipolar electrode pair.In one embodiment, at least one of the bipolar electrode pair isconfigured to be positioned to be expanded into contact with an innerwall of the hepatic artery branch upon expansion of the at least oneexpandable balloon. In one embodiment, the bipolar electrode pair isconfigured to deliver a thermal dose of energy configured to achievehepatic denervation. The at least one expandable balloon may beconfigured to maintain sufficient contact pressure between the at leastone electrode of the bipolar electrode pair and the inner wall of thehepatic artery branch. In some embodiments, the balloon cathetercomprises two expandable balloons, each having one electrode of thebipolar electrode pair disposed thereon. In one embodiment, the ballooncatheter comprises a single expandable balloon and the bipolar electrodepair is disposed on the expandable balloon. In one embodiment, theballoon comprises a cooling fluid within a lumen of the balloon.

In accordance with several embodiments, an apparatus configured forhepatic neuromodulation is provided. In one embodiment, the apparatuscomprises a catheter comprising a lumen and an open distal end and asteerable shaft configured to be slidably received within the lumen ofthe catheter. In one embodiment, at least a distal portion of thesteerable shaft comprises a shape memory material having a pre-formedshape configured to cause the distal portion of the steerable shaft tobend to contact a vessel wall upon advancement of the distal portion ofthe steerable shaft out of the open distal end of the catheter. In oneembodiment, a distal end of the steerable shaft comprises at least oneelectrode that is configured to be activated to deliver a thermal doseof energy configured to achieve denervation of a branch of a hepaticartery or other target vessel. In one embodiment, the shape memorymaterial of the steerable shaft is sufficiently resilient to maintainsufficient contact pressure between the at least one electrode and aninner wall of the branch of the hepatic artery during a hepaticdenervation procedure. The outside diameter at a distal end of thecatheter may be smaller than the outside diameter at a proximal end ofthe catheter to accommodate insertion within vessels having a smallinner diameter. In various embodiments, the outside diameter at thedistal end of the catheter is between about 1 mm and about 4 mm. In oneembodiment, the at least one electrode comprises a coating having one ormore windows.

In accordance with several embodiments, a neuromodulation kit isprovided. In one embodiment, the kit comprises a neuromodulationcatheter configured to be inserted within a vessel of the hepatic systemfor modulating nerves surrounding the hepatic artery. In one embodiment,the kit comprises a plurality of energy delivery devices configured tobe inserted within the lumen of the neuromodulation catheter. In oneembodiment, each of the energy delivery devices comprises at least onemodulation element at or near a distal end of the energy deliverydevice. In one embodiment, each of the energy delivery devices comprisesa distal portion comprising a different pre-formed shape memoryconfiguration. The at least one modulation element may be configured tobe activated to modulate at least a portion of the nerves surroundingthe hepatic artery to treat symptoms associated with diabetes.

In several embodiments, the invention comprises modulation of thenervous system to treat disorders affecting insulin and/or glucose, suchas insulin regulation, glucose uptake, metabolism, etc. In someembodiments, nervous system input and/or output is temporarily orpermanently modulated (e.g., decreased). Several embodiments areconfigured to perform one or a combination of the following effects:ablating nerve tissue, heating nerve tissue, cooling the nerve tissue,deactivating nerve tissue, severing nerve tissue, cell lysis, apoptosis,and necrosis. In some embodiments, localized neuromodulation isperformed, leaving surrounding tissue unaffected. In other embodiments,the tissue surrounding the targeted nerve(s) is also treated.

In accordance with several embodiments, methods of hepatic denervationare performed with shorter procedural and energy application times thanrenal denervation procedures. In several embodiments, hepaticdenervation is performed without causing pain or mitigates pain to thesubject during the treatment. In accordance with several embodiments,neuromodulation (e.g., denervation or ablation) is performed withoutcausing stenosis or thrombosis within the target vessel (e.g., hepaticartery). In embodiments involving thermal treatment, heat lost to theblood stream may be prevented or reduced compared to existingdenervation systems and methods, resulting in lower power and shortertreatment times. In various embodiments, the methods of neuromodulationare performed with little or no endothelial damage to the targetvessels. In several embodiments, energy delivery is deliveredsubstantially equally in all directions (e.g., omnidirectionaldelivery). In various embodiments of neuromodulation systems (e.g.,catheter-based energy delivery systems described herein), adequateelectrode contact with the target vessel walls is maintained, therebyreducing power levels, voltage levels and treatment times.

For purposes of summarizing the disclosure, certain aspects, advantages,and novel features of embodiments of the invention have been describedherein. It is to be understood that not necessarily all such advantagesmay be achieved in accordance with any particular embodiment of theinvention disclosed herein. Thus, the embodiments disclosed herein maybe embodied or carried out in a manner that achieves or optimizes oneadvantage or group of advantages as taught or suggested herein withoutnecessarily achieving other advantages as may be taught or suggestedherein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the anatomy of a target treatment location includingthe liver and hepatic blood supply, in accordance with an embodiment ofthe invention.

FIG. 2 illustrates various arteries supplying blood to the liver and itssurrounding organs and tissues and nerves that innervate the liver andits surrounding organs and tissues.

FIG. 3 illustrates a schematic drawing of a common hepatic artery andnerves of the hepatic plexus.

FIGS. 4A-4C, 5A and 5B, 6 and 7 illustrate embodiments of compressionmembers configured to facilitate modulation of nerves.

FIGS. 8 and 9 illustrate embodiments of neuromodulation catheters.

FIGS. 10 and 11 illustrate embodiments of electrode catheters.

FIGS. 12A and 12B illustrate embodiments of ablation coils.

FIGS. 13A-13C, 14A and 14B illustrate embodiments of energy deliverycatheters.

FIG. 15 illustrates several embodiments of catheter distal tip electrodeand guide wire shapes.

FIGS. 16A and 16B illustrate an embodiment of a windowed ablationcatheter.

FIG. 17 illustrates an embodiment of a balloon-based volume ablationcatheter system.

FIG. 18 illustrates an embodiment of a microwave-based ablation cathetersystem.

FIG. 19 illustrates an embodiment of an induction-based ablationcatheter system.

FIG. 20 illustrates an embodiment of a steam ablation catheter.

FIG. 21 illustrates an embodiment of a hot water balloon ablationcatheter.

FIGS. 22A-22D illustrate geometric models.

FIGS. 23A and 23B illustrate graphs of data from hepatic denervationstudies, in accordance with embodiments of the invention.

DETAILED DESCRIPTION I. Introduction and Overview

Embodiments of the invention described herein are generally directed totherapeutic neuromodulation of targeted nerve fibers to treat, or reducethe risk of occurrence or progression of, various metabolic diseases,conditions, or disorders, including but not limited to diabetes (e.g.,diabetes mellitus). While the description sets forth specific details invarious embodiments, it will be appreciated that the description isillustrative only and should not be construed in any way as limiting thedisclosure. Furthermore, various applications of the disclosedembodiments, and modifications thereto, which may occur to those who areskilled in the art, are also encompassed by the general conceptsdescribed herein.

The autonomic nervous system includes the sympathetic andparasympathetic nervous systems. The sympathetic nervous system is thecomponent of the autonomic nervous system that is responsible for thebody's “fight or flight” responses, those that can prepare the body forperiods of high stress or strenuous physical exertion. One of thefunctions of the sympathetic nervous system, therefore, is to increaseavailability of glucose for rapid energy metabolism during periods ofexcitement or stress, and to decrease insulin secretion.

The liver can play an important role in maintaining a normal bloodglucose concentration. For example, the liver can store excess glucosewithin its cells by forming glycogen, a large polymer of glucose. Then,if the blood glucose concentration begins to decrease too severely,glucose molecules can be separated from the stored glycogen and returnedto the blood to be used as energy by other cells. The liver is a highlyvascular organ that is supplied by two independent blood supplies, onebeing the portal vein (as the liver's primary blood supply) and theother being the hepatic artery (being the liver's secondary bloodsupply).

The process of breaking down glycogen into glucose is known asglycogenolysis, and is one way in which the sympathetic nervous systemcan increase systemic glucose. In order for glycogenolysis to occur, theenzyme phosphorylase must first be activated in order to causephosphorylation, which allows individual glucose molecules to separatefrom branches of the glycogen polymer. One method of activatingphosphorylase, for example, is through sympathetic stimulation of theadrenal medulla. By stimulating the sympathetic nerves that innervatethe adrenal medulla, epinephrine is released. Epinephrine then promotesthe formation of cyclic AMP, which in turn initiates a chemical reactionthat activates phosphorylase. An alternative method of activatingphosphorylase is through sympathetic stimulation of the pancreas. Forexample, phosphorylase can be activated through the release of thehormone glucagon by the alpha cells of the pancreas. Similar toepinephrine, glucagon stimulates formation of cyclic AMP, which in turnbegins the chemical reaction to activate phosphorylase.

Another way in which the liver functions to maintain a normal bloodglucose concentration is through the process of gluconeogenesis. Whenthe blood glucose concentration decreases below normal, the liver willsynthesize glucose from various amino acids and glycerol in order tomaintain a normal blood glucose concentration. Increased sympatheticactivity has been shown to increase gluconeogenesis, thereby resultingin an increased blood glucose concentration.

The parasympathetic nervous system is the second component of theautonomic nervous system and is responsible for the body's “rest anddigest” functions. These “rest and digest” functions complement the“fight or flight” responses of the sympathetic nervous system.Stimulation of the parasympathetic nervous system has been associatedwith decreased blood glucose levels. For example, stimulation of theparasympathetic nervous system has been shown to increase insulinsecretion from the beta-cells of the pancreas. Because the rate ofglucose transport through cell membranes is greatly enhanced by insulin,increasing the amount of insulin secreted from the pancreas can help tolower blood glucose concentration. In some embodiments, stimulation ofthe parasympathetic nerves innervating the pancreas is combined withdenervation of sympathetic nerves innervating the liver to treatdiabetes or the symptoms associated with diabetes (e.g., high bloodglucose levels, high triglyceride levels, high cholesterol levels) lowinsulin secretion levels). Stimulation and/or denervation of sympatheticand/or parasympathetic nerves surrounding other organs or tissues mayalso be performed in combination.

FIG. 1 illustrates a liver 101 and vasculature of a target hepatictreatment location 100. The vasculature includes the common hepaticartery 105, the proper hepatic artery 110, the right hepatic artery 115,the left hepatic artery 120, the right hepatic vein 125, the lefthepatic vein 130, the middle hepatic vein 135, and the inferior venacava 140. In the hepatic blood supply system, blood enters the liver bycoursing through the common hepatic artery 105, the proper hepaticartery 110, and then either of the left hepatic artery 120 or the righthepatic artery 115. The right hepatic artery 115 and the left hepaticartery 120 (as well as the portal vein, not shown) provide blood supplyto the liver 101, and directly feed the capillary beds within thehepatic tissue of the liver 101. The liver 101 uses the oxygen providedby the oxygenated blood flow provided by the right hepatic artery 115and the left hepatic artery 120. Deoxygenated blood from the liver 101leaves the liver 101 through the right hepatic vein 125, the lefthepatic vein 130, and the middle hepatic vein 135, all of which emptyinto the inferior vena cava 140.

FIG. 2 illustrates various arteries surrounding the liver and thevarious nerve systems 200 that innervate the liver and its surroundingorgans and tissue. The arteries include the abdominal aorta 205, theceliac artery 210, the common hepatic artery 215, the proper hepaticartery 220, the gastroduodenal artery 222, the right hepatic artery 225,the left hepatic artery 230, and the splenic artery 235. The variousnerve systems 200 illustrated include the celiac plexus 240 and thehepatic plexus 245. Blood supply to the liver is pumped from the heartinto the aorta and then down through the abdominal aorta 205 and intothe celiac artery 210. From the celiac artery 210, the blood travelsthrough the common hepatic artery 215, into the proper hepatic artery220, then into the liver through the right hepatic artery 225 and theleft hepatic artery 230. The common hepatic artery 215 branches off ofthe celiac trunk. The common hepatic artery 215 gives rise to thegastric and gastroduodenal arteries. The nerves innervating the liverinclude the celiac plexus 240 and the hepatic plexus 245. The celiacplexus 240 wraps around the celiac artery 210 and continues on into thehepatic plexus 245, which wraps around the proper hepatic artery 220,the common hepatic artery 215, and may continue on to the right hepaticartery 225 and the left hepatic artery 230. In some anatomies, theceliac plexus 240 and hepatic plexus 245 adhere tightly to the walls(and some of the nerves may be embedded in the adventitia) of thearteries supplying the liver with blood, thereby renderingintra-to-extra-vascular neuromodulation particularly advantageous tomodulate nerves of the celiac plexus 240 and/or hepatic plexus 245. Inseveral embodiments, the media thickness of the vessel (e.g., hepaticartery) ranges from about 0.1 cm to about 0.25 cm. In some anatomies, atleast a substantial portion of nerve fibers of the hepatic arterybranches are localized within 0.5 mm to 1 mm from the lumen wall suchthat modulation (e.g., denervation) using an endovascular approach iseffective with reduced power or energy dose requirements. In someembodiments, low-power or low-energy (e.g., less than 10 W of poweroutput and/or less than 1 kJ of energy delivered to the inner wall ofthe target vessel or to the target nerves) intravascular energy deliverymay be used because the nerves are tightly adhered to or within theouter walls of the arteries supplying the liver with blood (e.g. hepaticartery branches).

With continued reference to FIGS. 1 and 2, the hepatic plexus 245 is thelargest offset from the celiac plexus 240. The hepatic plexus 245 isbelieved to carry primarily afferent and efferent sympathetic nervefibers, the stimulation of which can increase blood glucose levels by anumber of mechanisms. For example, stimulation of sympathetic nervefibers in the hepatic plexus 245 can increase blood glucose levels byincreasing hepatic glucose production. Stimulation of sympathetic nervefibers of the hepatic plexus 245 can also increase blood glucose levelsby decreasing hepatic glucose uptake. Therefore, by disruptingsympathetic nerve signaling in the hepatic plexus 245, blood glucoselevels can be decreased or reduced.

In several embodiments, any of the regions (e.g., nerves) identified inFIGS. 1 and 2 may be modulated according to embodiments describedherein. Alternatively, in one embodiment, localized therapy is providedto the hepatic plexus, while leaving one or more of these other regionsunaffected. In some embodiments, multiple regions (e.g., of organs,arteries, nerve systems) shown in FIGS. 1 and 2 may be modulated incombination (simultaneously or sequentially).

FIG. 3 is a schematic illustration of the nerve fibers of the hepaticplexus 300. A portion of the common hepatic artery 305 (or,alternatively, the proper hepatic artery) is shown with the hepaticplexus 300 wrapping around the artery. Some of the nerve fibers of thehepatic plexus may be embedded within the adventitia of the commonhepatic artery 305 (or proper hepatic artery), or at least tightlyadhered to or within the outer vascular walls. As shown, there is avessel luminal axis that follows the center of the artery lumen. Thehepatic plexus 300 is comprised of parasympathetic nerves 310 andsympathetic nerves 315. In some anatomies, the parasympathetic nerves310 tend to course down one half of the circumference of an artery andthe sympathetic nerves 315 tend to course down the other half of theartery.

As shown in FIG. 3, the portion of the common hepatic artery 305 isroughly cylindrical, with parasympathetic nerves 310 innervatingapproximately a 180° arc of the cylinder, and the sympathetic nerves ofthe hepatic plexus 315 innervating the opposite approximately 180° arcof the cylinder. In some anatomies, there is very little overlap (ifany) between the parasympathetic nerves 310 and the sympathetic nerves315 of the hepatic plexus. Such discretization may be advantageous inembodiments where only sympathetic nerves 315 or parasympathetic nerves310 of the hepatic plexus are to be modulated. In some embodiments,modulation of the sympathetic nerves 315 of the hepatic plexus may bedesirable while modulation of the parasympathetic nerves 310 of thehepatic plexus may not be desirable (or vice-versa).

In some embodiments, only selective regions of the adventitial layer oftarget vasculature is modulated. In some subjects, parasympathetic andsympathetic nerves may be distributed distinctly on or in theadventitial layer of blood vessels. For example, using an axis createdby the lumen of a blood vessel, parasympathetic nerves of the hepaticplexus may lie in one 180 degree arc of the adventitia while sympatheticnerves may lie in the other 180 degree arc of the adventitia, such asshown in FIG. 3. Generally, the sympathetic nerve fibers tend to runalong the anterior surface of the hepatic artery, while theparasympathetic nerve fibers are localized toward the posterior surfaceof the hepatic artery. In these cases, it may be advantageous toselectively disrupt either the sympathetic or the parasympathetic nervesby modulating nerves in either the anterior region or the posteriorregion.

In some subjects, sympathetic nerve fibers may run along a significantlength of the hepatic artery, while parasympathetic nerve fibers mayjoin toward the distal extent of the hepatic artery. Research has shownthat the vagus nerve joins the liver hilus near the liver parenchyma(e.g., in a more distal position than the nerves surrounding the hepaticarterial tree). As the vagal nerves are parasympathetic, the nervessurrounding the hepatic artery proximally may be predominantlysympathetic. In accordance with several embodiments, modulation (e.g.,ablation) of the proper hepatic artery towards its proximal extent(e.g., halfway between the first branch of the celiac artery and thefirst branch of the common hepatic artery) is performed when it isdesired to disrupt sympathetic nerves in the hepatic plexus. Ablation ofthe proximal extent of the hepatic artery could advantageously providethe concomitant benefit of avoiding such critical structures as the bileduct and portal vein (which approaches the hepatic artery as it coursesdistally towards the liver).

In one embodiment, only the anterior regions of the hepatic artery areselectively modulated (e.g., ablated). In one embodiment, approximately180 degrees of the arterial circumference is ablated. In someembodiments, it is desirable to ablate in the range of about 60° toabout 240°, about 80° to about 220°, about 100° to about 200°, about120° to about 180°, about 140° to about 160°, or overlapping rangesthereof. In some embodiments, the portion of the vessel wall not beingtargeted opposite the portion of the vessel wall being targeted isactively cooled during the modulation procedure. Such cooling maydecrease collateral injury to the nerve fibers not intended fortreatment. In many embodiments, cooling is not used.

In embodiments in which only selective portions of the vessel wall areto be treated, a zig-zag, overlapping semicircular, spiral, lasso, orother pattern of ablation may be used to treat only selective regions ofnerve tissue in the adventitia. An example of a spiral ablation patternZ, in accordance with one embodiment, is shown in FIG. 3. In someembodiments, one or more ablation electrodes having an inherent zig-zag,spiral or other pattern are used. In some embodiments, a single pointablation electrode (regardless of electrode pattern) is advancedlongitudinally and circumferentially about substantially 180 degrees ofthe vessel circumference to ablate in a zig-zag, spiral or otherpattern, thereby selectively ablating only approximately 180 degrees ofthe vessel wall and the accompanying nerve tissues. In some embodiments,other patterns of electrode configurations are used. In someembodiments, other patterns of ablation electrode movement (regardlessof inherent conformation) are used.

In some embodiments, where only selective regions of the vessel wall areto be modulated (e.g., ablated or stimulated) it may be helpful to havea high degree of catheter control, stability and/or precision. Toachieve the control necessary for a high degree of precision, a guidecatheter may be used to engage the osteum of a nearby branch (e.g., thebranch of the common hepatic artery off of the celiac artery) to providea constant reference point from which to position an ablation catheter.Alternatively, the catheter could also be anchored in other branches,either individually or simultaneously, to further improve control.Simultaneous anchoring may be achieved by means of a compliant,inflatable balloon (e.g., having a shape and size configured to match anosteum or another portion of a particular vessel), which maysubstantially occlude the vascular lumen (e.g., osteum), therebyanchoring the catheter and providing increased stability. Such anapproach may obviate the need for angiography to map the course oftreatment, including the concomitant deleterious contrast agent andx-ray exposure, because treatment guidance can be performed relative toa reference angiogram, with distance of the neuromodulation catheterfrom the guide catheter measured outside of the patient. In someembodiments, the inflatable balloon may have a size and shape configuredto engage multiple ostia or to be anchored in multiple branches.

The anatomy of the vascular branches distal of the celiac plexus may behighly disparate between subjects and variations in the course of thesympathetic and parasympathetic nerves tend to be associatedpredominantly with branches distal of the celiac plexus, rather thanbeing associated with any specific distance distally along the hepaticartery. In some embodiments, a neuromodulation location is selectedbased on a position relative to the branching anatomy rather than on anyfixed distance along the hepatic artery in order to target thesympathetic nerve fibers; for example, within the common hepatic arteryand about 1 cm-6 cm (e.g., about 2 cm-3 cm, or substantially at themidpoint of the common hepatic artery) from the branching of the celiacaxis.

Parasympathetic and sympathetic nerve fibers tend to have opposingphysiologic effects, and therefore, in some embodiments, only thesympathetic nerve fibers and not the parasympathetic nerve fibers aredisrupted (e.g., denervated, ablated) in order to achieve the effects ofreducing endogenous glucose production and increasing hepatic andperipheral glucose storage. In some embodiments, only theparasympathetic nerve fibers and not the sympathetic nerve fibers arestimulated in order to achieve the effects of reducing endogenousglucose production and increasing hepatic and peripheral glucosestorage. In some embodiments, the sympathetic nerve fibers aredenervated while the parasympathetic nerve fibers are simultaneouslystimulated in order to achieve the effects of reducing endogenousglucose production and increasing hepatic and peripheral glucosestorage. In some embodiments, the denervation of the sympathetic nervefibers and the stimulation of the parasympathetic nerve fibers areperformed sequentially.

In accordance with several embodiments, methods of therapeuticneuromodulation for preventing or treating disorders (such as diabetesmellitus) comprise modulation of nerve fibers (e.g., the sympatheticnerve fibers of the hepatic plexus). In one embodiment, neuromodulationdecreases hepatic glucose production and/or increases hepatic glucoseuptake, which in turn can result in a decrease of blood glucose levels.Disruption of the nerve fibers can be effected by ablating, denervating,severing, destroying, removing, desensitizing, disabling, reducing,crushing or compression, or inhibiting neural activity through,blocking, or otherwise modulating (permanently or temporarily) the nervefibers or surrounding regions. In some embodiments, the disruption iscarried out using one or more energy modalities. Energy modalitiesinclude, but are not limited to, microwave, radiofrequency (RF) energy,thermal energy, electrical energy, ultrasonic energy, focused ultrasoundsuch as high-intensity or low-intensity focused ultrasound, laserenergy, phototherapy or photodynamic therapy (e.g., in combination withone or more activation agents), ionizing energy delivery (such as X-ray,proton beam, gamma rays, electron beams, and alpha rays), cryoablation,and chemoablation, or any combination thereof. In some embodiments, thedisruption of the sympathetic nerve fibers is carried out by chemicalsor therapeutic agents (for example, via drug delivery), either alone orin combination with an energy modality. In some embodiments, ionizingenergy is delivered to a target region to prevent regrowth of nerves.

In accordance with several embodiments disclosed herein, the inventioncomprises modulation of nerve fibers instead of or in addition to nervefibers in the hepatic plexus to treat diabetes or other metabolicconditions, disorders, or other diseases. For example, sympathetic nervefibers surrounding the common hepatic artery proximal to the properhepatic artery, sympathetic nerve fibers surrounding the celiac artery(e.g., the celiac ganglion or celiac plexus, which supplies nerve fibersto multiple organs including the pancreas, stomach, and smallintestine), sympathetic nerve fibers that innervate the pancreas,sympathetic nerve fibers that innervate fat tissue (e.g., visceral fat),sympathetic nerve fibers that innervate the adrenal glands (e.g., therenal plexus or suprarenal plexus), sympathetic nerve fibers thatinnervate the gut, stomach or small intestine (e.g., the duodenum),sympathetic nerve fibers that innervate brown adipose tissue,sympathetic nerve fibers that innervate skeletal muscle, the vagalnerves, the phrenic plexus or phrenic ganglion, the gastric plexus, thesplenic plexus, the splanchnic nerves, the spermatic plexus, thesuperior mesenteric ganglion, the lumbar ganglia, the superior orinferior mesenteric plexus, the aortic plexus, or any combination ofsympathetic nerve fibers thereof may be modulated in accordance with theembodiments herein disclosed. In some embodiments, instead of beingtreated, these other tissues are protected from destruction duringlocalized neuromodulation of the hepatic plexus. In some embodiments,one or more sympathetic nerve fibers (for example, a ganglion) can beremoved (for example, pancreatic sympathectomy). The nerves (sympatheticor parasympathetic) surrounding the various organs described above maybe modulated in a combined treatment procedure (either simultaneously orsequentially).

In some embodiments, modulation of the nerves (e.g., sympatheticdenervation) innervating the stomach results in reduction of ghrelinsecretion and greater satiety, decreased sympathetic tone leading toincreased motility and/or faster food transit time, thereby effecting a“neural gastric bypass.” In some embodiments, modulation of the nerves(e.g., sympathetic denervation) innervating the pylorus results indecreased efferent sympathetic tone, leading to faster transit time andeffecting a “neural gastric bypass.” In some embodiments, modulation ofthe nerves (e.g., sympathetic denervation) innervating the duodenumresults in disrupted afferent sympathetic activity leading to alteredsignaling of various receptors and hormones (e.g., GLP-1, GIP, CCK, PYY,5-HT), thereby causing increased insulin secretion and insulinsensitivity, and/or decreased efferent sympathetic tone leading tofaster transit time, thereby effecting a “neural duodenal bypass.”

In some embodiments, modulation of the nerves (e.g., sympatheticdenervation) innervating the pancreas results in decreased efferentsympathetic tone, thereby causing increased beta cell insulin productionand beta cell mass, and decreased alpha cell glucagon production. Insome embodiments, modulation of the afferent sympathetic nervesinnervating the liver results in reflexive decreased sympathetic tone tothe pancreas, GI tract, and/or muscle. In some embodiments, modulationof the afferent sympathetic nerves innervating the liver results in anincrease in a hepatokine hormone with systemic effects (e.g., hepaticinsulin sensitizing substance. In some embodiments, stimulation of thecommon hepatic branch of the vagus nerves could result in similareffects.

II. Types of Neuromodulation

A. Mechanical Neuromodulation

The selective modulation or disruption of nerve fibers may be performedthrough mechanical or physical disruption, such as, but not limited to,cutting, ripping, tearing, or crushing. Several embodiments of theinvention comprise disrupting cell membranes of nerve tissue. Severalembodiments involve selective compression of the nerve tissue andfibers. Nerves being subjected to mechanical pressure, such as, but notlimited to, selective compression or crushing forces may experienceeffects such as, but not limited to, ischemia, impeded neural conductionvelocity, and nervous necrosis. Such effects may be due to a pluralityof factors, such as decreased blood flow.

In several embodiments, many of the effects due to selective compressionor mechanical crushing forces are reversible. Beyond using mechanicalcompression to selectively and reversibly modulate neural response,mechanical compression may be used to permanently modulate neuralresponse through damage to select myelin sheaths and individual nervefascicles. In some embodiments, the level of neural modulation is tunedby modulating the mechanical compressive forces applied to the nerve.For example, a large compressive force applied to a nerve may completelyinhibit neural response, while a light compressive force applied to thesame nerve may only slightly decrease neural response. In someembodiments, a mechanical compressive force or crushing force may beapplied to a nerve, such as a sympathetic nerve in the hepatic plexus,with a removable crushing device. In some embodiments, the removablecrushing device is removed and replaced with a stronger or weakerremovable crushing device depending on the individual needs of thesubject (e.g., the strength of the removable crushing device being keyedto the needed neural response levels). The ability of such removablecrushing devices to be fine-tuned to selectively modulate neuralresponse is advantageous over the binary (e.g., all or nothing) responseof many types of neural ablation.

In various embodiments, the compressive or crushing forces necessary tocompress or crush nerves or cause ischemia within the hepatic artery orother vessels may range from about 1 to about 100 g/mm², from about 1g/mm² to about 10 g/mm², from about 3 g/mm² to about 5 g/mm² (e.g., 8g/mm²), from about 5 g/mm² to about 20 g/mm², from about 10 g/mm² toabout 50 g/mm², from about 20 g/mm² to about 80 g/mm², from about 50g/mm² to about 100 g/mm², or overlapping ranges thereof. Thesecompressive forces may be effected by the various embodiments ofmechanical neuromodulation devices or members described herein.

FIGS. 4A-4C, 5A, 5B, 6 and 7 illustrate various embodiments ofmechanical neuromodulation devices or members. FIGS. 4A-4C illustrateembodiments of a shape memory compression clip 400. In some embodiments,the shape memory compression clip 400 is used to mechanically compresstarget nerves. In some embodiments, the shape memory compression clip400 is removable. FIG. 4A illustrates a resting conformation of theshape memory compression clip 400. FIG. 4B illustrates a strainedconformation of the shape memory compression clip 400, which looks likea capital “U” in the illustrated embodiment The shape memory compressionclip 400 may be applied to a nerve, such as a nerve of the hepaticplexus by forcibly placing the shape memory compression clip 400 in itsstrained conformation, placing the target nerve in the bottom well ofthe shape memory compression clip 400, and then allowing the shapememory compression clip 400 to return to its resting conformation,thereby applying the desired compressive forces to the target nerve bycausing it to be crushed or pinched. FIG. 4C illustrates an alternativeembodiment of a shape memory compression clip 420 in which the bottomwell forms an acute bend instead of being curvate when in a restingshape. The compression clip 400, 420 may be allowed to return to aresting configuration through either removal of external forces biasingthe compression clip in a strained configuration (e.g., utilizingsuperelastic properties of shape memory materials) or heating thecompression clip above a transition temperature, thereby allowing thecompression clip to assume a native or resting configuration in anaustenitic phase above the transition temperature.

In some embodiments, mechanical compressive forces are held atsubstantially constant levels after application. In some embodiments,the shape memory compression clip 400 may be tailored to the anatomy ofdifferent target nerves. In some embodiments, the shape memorycompression clip 400 varies in size or shape to compensate foranatomical variance. In some embodiments, varying sizes or shapes ofshape memory compression clips may be used, in addition to compensatingfor anatomical variance, to selectively apply varying levels ofcompressive stresses to the target nerve (e.g., smaller clip or strongermaterial for higher forces and larger clip or weaker material forsmaller forces). In one embodiment, the shape memory material isnitinol. In various embodiments, the shape memory material is a shapememory polymer or any other appropriate material having shape memorymaterial properties. In some embodiments, compression members comprisesimple spring clips or any other devices capable of applying asubstantially constant force. In some embodiments, a compression memberis configured to clamp the entire artery and the nerves in theadventitial layer, thereby applying the desired compressive forces toboth the target nerves and the artery around which the target nervestravel.

Applying compressive forces to hepatic arteries is uniquely feasible, insome embodiments, because the liver is supplied with blood from both thehepatic arteries, around which many of the target nerves describedherein may travel, as well as the portal vein. If at least one of thehepatic arteries is clamped (for the purpose of applying compressiveforces to the nerves in its adventitia), the liver would lose the bloodsupply from that artery, but would be fully supplied by the portal vein,thereby leaving the liver viable and healthy.

In some embodiments, mechanical compressive forces are variable acrosstime following application. In some embodiments, the mechanicalcompressive forces are varied according to a pre-set duty cycle, therebytitrating the effects of the neuromodulation. One or more embodimentsmay comprise a transcutaneous delivery of energy to a circuit coupled toa compression member (e.g., a nitinol clip) having a transition betweenmartensitic and austenitic states at a specific temperature induced by atemperature that is substantially different from body temperature. Inseveral embodiments, a variance in temperature is provided through, butis not limited to: a thermocouple (e.g., a Peltier junction) thermallycoupled to the compression member to which the circuit may apply power,or a heating element thermally coupled to the compression member towhich the circuit may apply resistive power, thereby altering thephysical conformation of the compression member and varying (eitherincreasing or decreasing depending on the power applied) the compressiveforces generated by the compression member. In one embodiment, thecompression member itself acts as a resistive element and the circuit iscoupled directly to the compression member to apply resistive power tothe compression member, thereby altering the physical conformation ofthe compression member and varying (either increasing or decreasingdepending on the power applied) the compressive forces generated by thecompression member. Other embodiments combine the compression memberwith a thermocouple to allow the selective application of electric powerto vary the compressive stresses created by the compression member.

FIGS. 5A and 5B illustrate another embodiment of a compression device.FIG. 5A illustrates a catheter-based vascular wall compression system500 including a vascular wall clamp 515 in an open conformation. Thecatheter-based vascular wall compression system 500 includes adetachable insertion catheter 505, suction holes 510, an engagementportion 515A of the vascular wall clamp 515, an anchoring mechanism 520,a receiving portion 515B of the vascular wall clamp, and an anchoringmechanism accepting portion 530. In operation, the vascular wall clamp515 may be inserted into the target vessel on the distal end of thedetachable insertion catheter 505. In one embodiment, the receivingportion 515B of the vascular wall clamp 515 is located at the distal endof the detachable insertion catheter 505, while the engagement portion515A of the vascular wall clamp 515 is located slightly proximal to thereceiving portion 515B. The surface of the detachable insertion catheter505 between the receiving portion 515B and the engagement portion 515Amay include a plurality of suction holes 510.

In further operation, once the vascular wall clamp 515 is placed at thedesired target location, the suction holes 510, in one embodiment,create a vacuum, or suction, which brings the walls of the target vesselin substantially direct apposition to the surface of the detachableinsertion catheter portion that includes the plurality of suction holes510. While maintaining suction, and therefore the position of the vesselwall in apposition to the detachable insertion catheter 505, theengagement portion 515A is moved toward the receiving portion 515B (orvice versa), thereby pinching the vascular wall which remained in directapposition to the detachable insertion catheter between the receivingportion 515B and the engagement portion 515A.

The anchoring mechanism 520, which is attached to the engagement portion515A engages the anchoring member accepting portion 530 of the receivingportion 515B, thereby securing the receiving portion 515B to theengagement portion 515A and clamping the vascular wall portion thatremains in direct apposition to the detachable insertion catheter 505between the receiving portion 515B and the engagement portion 515A. Oncethe receiving portion 515B has fully engaged with the engagement portion515A, the detachable insertion catheter 505 may be disengaged from thevascular wall clamp 515 and removed by the same path it was inserted.

FIG. 5B illustrates the vascular wall clamp 515 in a closedconformation. In FIG. 5B, the anchoring mechanism 520, which is attachedto the engagement portion 515A of the vascular wall clamp 515 hasengaged the anchoring member accepting portion 530 of the receivingportion 515B of the vascular wall clamp 515, thereby clamping a portionof the vascular wall between the receiving portion 515B and theengagement portion 515A. FIG. 5B shows that the detachable insertioncatheter 505 has already been removed.

In some embodiments, the engagement portion 515A and the receivingportion 515B of the vascular wall clamp 525 both include a hollowcenter. In these embodiments, when the detachable insertion catheter 505is removed, the hole at the center of the engagement portion 515A of thevascular wall clamp 515 and the hole at the center of the receivingportion 515B of the vascular wall clamp 525 creates a patent lumenbetween the receiving portion 515B and the engagement portion 515A,thereby allowing continued blood flow from one side to the other. Insome embodiments, the detachable insertion catheter 505 is attached toeither the engagement portion 515A or the receiving portion 515B of thevascular wall clamp 515 by means of a threaded portion, which may beunthreaded once the receiving portion 515B and engagement portion 515Ahave engaged, and the detachable insertion catheter 505 is no longerneeded.

In some embodiments, the vascular wall clamp 515 is inserted to thetarget anatomy using an over-the-wire approach. In some embodiments, thedetachable insertion catheter 505 is hollow and has suction holes 510 incommunication with an internal hollow lumen of the detachable insertioncatheter 505. The suction holes 510 may be a series of small openings, ascreen, or any other structure which allows a lower pressure area to becreated between the receiving portion 515B and the engagement portion515A of the vascular wall clamp 515 to bring the vessel wall andperivascular tissue in substantially direct apposition with thedetachable insertion catheter 505. In some embodiments, the vascularwall clamp 515 is deployed by pulling proximally on the detachableinsertion catheter 505, thereby bringing the distal receiving portion515B of the vascular wall clamp 525 into engagement with the proximalengagement portion 515A of the vascular wall clamp 515, therebycompressing and/or severing arterial and nerve tissue captured therein.In some embodiments, rotation of the catheter 505 is effective todisengage the catheter 505 from the vascular wall clamp 515. In someembodiments, removal of the detachable insertion catheter 505 from thevascular wall clamp 515 leaves a patent lumen permitting blood flow tothe liver.

In some embodiments, the engagement mechanism 520 comprises at least onespear-shaped clip and the engagement accepting portion 530 comprises atleast one hole aligned to accept the at least one spear shaped clip andto engage the two the at least one spear shaped clip engagementmechanism 520 enters the at least one hole engagement accepting portion530 and snaps into place. In some embodiments, the engagement mechanism520 and engagement accepting portion 530 are simply magnets which holdthe receiving portion 515B of the vascular wall clamp 515 and theengagement portion 515A of the vascular wall clamp 515 together. Instill other embodiments, the engagement mechanism 520 and the engagementaccepting portion 530 are any structures that allow the engagementportion 515A to engage the receiving portion 515B and remain in thatengaged conformation. In some embodiments, the vascular wall clamp 515comprises a biologically inert material with decreased thrombogenicity,such as Teflon®.

FIG. 6 illustrates an embodiment of an extravascular compression coil600 inserted within a vessel. In operation, the extravascularcompression coil 600 may be advanced through a hole in the vascular wall610 in a spiraling intra-vascular to extra-vascular manner into thevessel adventitia, thereby placing the extravascular compression coil600 around the target vessel. In some embodiments, the extravascularcompression coil 600 has the effect of compressing the nerves locatedwithin the vascular wall of the target vessel. In some embodiments, toprevent occlusion and stenosis, an intravascular stent is subsequentlyplaced within the lumen of the target vessel, thereby both propping openthe vessel for continued flow and providing a resilient surface againstwhich the target nerves may be compressed.

In embodiments where stenosis is of particular concern, a stent isplaced in the target vessel after treatment to retain patency. In someembodiments, the placement of a stent with in the lumen of the targetvessel provides the added benefit of compressing the vascular wall to ahigher degree, thereby disrupting the target nerves even more. In someembodiments, a stent is placed in the portal vein due to the risk ofportal vein stenosis from hepatic arterial ablation procedures. In someembodiments, to protect the portal vein from possible stenosis, analcooling is used because the gut venous flow travels to the portal system(in some embodiments, anal cooling has the direct result of cooling theportal vein and decreasing the likelihood of stenosis due to treatmentof the hepatic artery).

In some embodiments, magnets may be delivered separately into the portalvein and hepatic artery. Upon placement of the two magnets, oppositepoles of the two magnets will attract each other and subsequently mate,thereby resulting in substantial compression of the nerves disposedbetween the two magnets. The force created by the mating of the twomagnets may be selectively modulated by increasing or decreasing thestrength of magnets used for any given patient morphology, as desired orrequired.

FIG. 7 illustrates an embodiment of a fully occluding balloon 700inserted within a target blood vessel. In operation, a fully occludingballoon 710 is inserted into a target vessel, inflated and used toexpand or stretch the vascular lumen to sufficiently stretch thesurrounding nerves to either the point of ischemia or physicaldisruption. The fully occluding balloon 710 may be removed afterphysical disruption or after the target nerves have been destroyed dueto ischemia. Alternatively, the fully occluding balloon 710 may be leftin place permanently because, as discussed previously, the liver issupplied by blood from the portal vein as well, rendering the hepaticartery at least somewhat redundant. In some embodiments, the level ofballoon compression is adjusted in an ambulatory fashion, therebyallowing for titration of the neuromodulation effect.

In some embodiments, rather than using a fully occluding balloon 710, anon-occluding balloon or partially occluding balloon is inserted into atarget vessel, inflated, and used to expand or stretch the vascularlumen to sufficiently stretch the surrounding nerves to the point ofischemia or physical disruption. The non-occluding or partiallyoccluding balloon may have similar structural features as the fullyoccluding balloon 710, but may include at least one hollow lumen (e.g.,a central lumen) to allow for continued blood flow after placement. Insome embodiments, the level of balloon compression can be adjusted in anambulatory fashion, thereby allowing for titration of theneuromodulation effect.

In some embodiments, similar to the occlusion techniques describedabove, a balloon catheter may be inserted into the target vessel andthen filled with a fluid which is infused and withdrawn at a specificfrequency (e.g., pressurized in an oscillating fashion), thereby causingmechanical disruption of the nerve fibers surrounding the target vessel(e.g., hepatic artery). In some embodiments, the fluid used to fill theballoon catheter may be a contrast agent to aid in visualization of thearterial structure (and thereby limiting the amount of contrast agentused in the procedure).

In some embodiments, a fluid is injected into the interstitial spacesurrounding the vasculature around which the target nerve lies, therebyapplying compressive forces to the nerve bundle which surrounds thevessel(s). In some embodiments, the fluid is air. In some embodiments,the fluid is any noble gas (e.g., heavy gas), including but not limitedto: helium, neon, argon, krypton, and xenon. In some embodiments, thefluid is nitrogen gas. In some embodiments, the fluid is any fluidcapable of being injected to apply the desired compressive forces. Insome embodiments, the fluid is injected by a catheter insertedtransluminally through a blood vessel in substantially close proximityto the target site (e.g., location where nervous compression isdesired). In some embodiments, the fluid is injected by a needle ortrocar inserted transdermally through the skin and surrounding tissuesto the target site. Any method of fluid injection may be used to deliverthe requisite amount of fluid to the target site in order to createcompressive forces that are applied to the target nerve, such as nervesof the hepatic plexus.

In some embodiments, a target vessel is completely transected, therebycausing a complete and total physical disruption of the vessel wall andthe surrounding nerves in the adventitial tissues. The target vessel maythen be re-anastamosed, thereby allowing continued perfusion through thevessel. The nerve tissue either does not reconnect, or takes asignificant amount of time to do so. Therefore, all neural communicationsurrounding the transected vessel may temporarily or permanently thedisrupted. In some embodiments, a cutting device is advanced in acatheter through the subject's vasculature until it reaches a targetvessel. The cutting device may then be twisted along the axis of thetarget vessel to cut through the target vessel from the inside out. Insome embodiments, an expandable element, such as a balloon catheter, isinserted into the vessel to compress the vessel wall and provide acontrolled vessel thickness to permit transection. A rotational cuttermay then be advanced circumferentially around the expandable element toeffect transection of the vessel and the nerves disposed within theadventitia of the vessel. In one embodiment, the target vessel istransected during open surgery.

Re-anastomoses of vessels could be achieved using any of severalmethods, including laser, RF, microwave, direct thermal, or ultrasonicvessel sealing. In some embodiments, thermal energy may be deliveredthrough an expandable element to effect anastomosis of the vessel underthe mechanical pressure provided by the expandable element. Thecombination of pressure, time, and temperature (e.g., 60° C., 5 seconds,and 120 psi in one embodiment) may be an effective means to seal vesselssuch as the hepatic arteries.

B. Catheter-Based Neuromodulation

In accordance with some embodiments, neuromodulation (e.g., thedisruption of sympathetic nerve fibers) is performed using a minimallyinvasive catheter system, such as an ablation catheter system. In someembodiments, an ablation catheter system for ablating nerve fibers isintroduced using an intravascular (e.g., intra-arterial) approach. Inone embodiment, an ablation catheter system is used to ablatesympathetic nerve fibers in the hepatic plexus. As described above, thehepatic plexus surrounds the proper hepatic artery, where it branchesfrom the common hepatic artery. In some embodiments, the ablationcatheter system is introduced via an incision in the groin to access thefemoral artery. The ablation catheter system may be advanced from thefemoral artery to the proper hepatic artery via the iliac artery, theabdominal aorta, the celiac artery, and the common hepatic artery. Inother embodiments, any other suitable percutaneous intravascularincision point or approach is used to introduce the ablation cathetersystem into the arterial system (e.g., a radial approach via a radialartery or a brachial approach via a brachial artery).

In some embodiments, the catheter may be placed into the target regionsubstantially close to the target nerve through percutaneous injection.Using such a percutaneous placement may allow less destructive, lessinvasive selective destruction or disruption of the target nerve.

In some embodiments, the catheter system comprises a visualizationdevice substantially close to the distal end of the catheter. Thevisualization device may promote nervous visualization, thereby possiblyallowing higher levels of precision in targeted nervous disruption. Insome embodiments, the catheter system comprises a light sourceconfigured to aid in visualization. In some embodiments, a light sourceand a visualization device (such as a camera) are used in tandem topromote visibility. In some embodiments, the catheter system comprises adistal opening out of which active elements (such as any camera, light,drug delivery port, and/or cutting device, etc.) are advanced. In someembodiments, the catheter system comprises a side opening out of whichthe active elements (such as any camera, light, drug delivery port,and/or cutting device, etc.) may be advanced, thereby allowing the userto access the vessel wall in vessels with tortuous curves and therebyallowing nerve destruction with the axis of the catheter alignedparallel to the vessel.

Animal studies have shown that the force of electrode contact againstthe vessel wall may be a critical parameter for achieving ablativesuccess in some embodiments. Therefore, ablation catheter devices mayadvantageously not only be small enough to access the targetvasculature, but also to incorporate low-profile features forfacilitating sufficient electrode contact pressure during the length ofthe treatments.

In some embodiments, the catheter of the catheter system has a diameterin the range of about 2-8 Fr, about 3-7 Fr, about 4-6 Fr (includingabout 5 Fr), and overlapping ranges thereof. The catheter may have avarying diameter along its length such that the distal portion of thecatheter is small enough to fit into progressively smaller vessels asthe catheter is advanced within vasculature. In one embodiment, thecatheter has an outside diameter sized to fit within the common hepaticartery (which may be as small as about 1 mm) or the proper hepaticartery. In some embodiments, the catheter is at least about 150 cm long,at least about 140 cm long, at least about 130 cm long, at least about120 cm long, at least about 110 cm long, at least about 100 cm long, orat least about 90 cm long. In some embodiments, the flexibility of thecatheter is sufficient to navigate tortuous hepatic arterial anatomyhaving bend radii of about 10 mm, about 9 mm, about 8 mm, about 7 mm,about 6 mm, about 5 mm, about 4 mm, about 3 mm, about 2 mm, about 1 mm,or about 0.5 mm.

In accordance with several embodiments, catheters of the catheter-basedsystems described herein have steerable, pre-curved, deflectable orflexible distal tip components or distal segments. The deflectability orflexibility may advantageously bias an energy applicator against thearterial wall to ensure effective and/or safe delivery of therapy,permit accurate positioning of the energy applicator, maintain contactof an energy delivery element against a vascular wall maintainsufficient contact pressure with a vascular wall, and/or help navigatethe catheter to the target anatomy. In some embodiments, catheters withsteerable, curvable or articulatable or distal portions provide theability to cause articulation, bending, or other deployment of thedistal tip (which may contain an ablation element or energy deliveryelement) even when a substantial portion of the catheter remains withina guide catheter. In some embodiments, the neuromodulation cathetersprovide the ability to be delivered over a guidewire, as placing guidecatheters may be unwieldy and time-consuming to navigate.

In various embodiments, the contact force exerted on the vessel wall tomaintain sufficient contact pressure is between about 1 g to about 500g, from about 20 g to about 200 g, from about 10 g to about 100 g, fromabout 50 g to about 150 g, from about 100 g to about 300 g, from about200 g to about 400 g, from about 300 g to about 500 g, or overlappingranges thereof. In some embodiments, the same ranges may be used butexpressed as g/mm² numbers. The contact pressures described above may beachieved by any of the neuromodulation (e.g., ablation) devices andsystems described herein.

FIG. 8 illustrates an embodiment of a steerable neuromodulation catheter800 having an articulatable tip. The neuromodulation catheter 800comprises a catheter body 805, multiple segments 810, multiplecorresponding hinges 820, and multiple corresponding articulation wires830. In some embodiments, the neuromodulation catheter 800 includesfewer than six segments, hinges, and/or articulation wires (e.g., two,three, four, or five). In some embodiments, the neuromodulation catheter800 includes more than six segments, hinges, and/or articulation wires(e.g., seven, eight, nine, ten, eleven to twenty, or more than twenty).In one embodiment, the segments 810 and the hinges 820 are hollow.

Each of the segments 810 is coupled to adjacent segment(s) by one of thehinges 820. Each of the articulation wires is attached to one of thesegments and passes from the segment to which it is attached through theother segments toward the catheter body 805. In operation, thearticulation wires may be extended or retracted as desired, therebypivoting the articulatable tip of the catheter 800.

In some embodiments, all of the articulation wires 830 are extended andretracted in combination. In other embodiments, each of the articulationwires 830 is individually actuatable. In such embodiments, eachindividual segment 810 could be individually actuatable by eachcorresponding articulation wire 830. For example, even when the thirdsegment, the fourth segment, the fifth segment, and the sixth segmentare constrained within a guide catheter, the first segment and thesecond segment may be articulated by extending or retracting the firstarticulation wire and/or the second articulation wire, respectively,with sufficient force. The steerable catheter 800 may advantageouslypermit improved contact pressure between the distal tip of the steerablecatheter 800 and the vascular wall of the target vessel, therebyimproving treatment efficacy.

FIG. 9 illustrates an embodiment of a neuromodulation catheter 900 witha deflectable distal tip. The neuromodulation catheter 900 comprises aguidewire configured to facilitate steerability. The neuromodulationcatheter 900 includes an ablation catheter tip 905, a guidewire housing910, a guide wire channel 915, and a guidewire 920. In operation, theguidewire 920 may be extended out through guide wire channel 915 to beused in its guiding capacity to navigate through vasculature. When it isnot desirable to use the guidewire 920 in its guiding capacity, theguide wire 920 may be retracted into the ablation catheter tip 905 andthen extended into the guide wire housing 910, where it may be storeduntil needed or desired.

In some embodiments, the guidewire 920 is plastically deformable with apermanent bend in the distal tip. In such embodiments, the guidewire 920may be rotated within the body of the neuromodulation catheter 900 toplastically deform and be pushed into the guide wire housing 910, or maybe rotated 180 degrees and regain its bent configuration to exit throughthe guide wire channel 915. In some embodiments, a thermocoupletemperature sensor may be incorporated into the guide wire 920. In someembodiments, the guide wire 920 is used to deliver ablative energy (suchas RF energy) to at least one electrode. In one embodiment, delivery ofthe ablative energy is facilitated by disposing a conductive gel betweenthe guidewire and the at least one ablation electrode.

In some embodiments, a catheter system is configured to extravascularlyand selectively disrupt target nerves. In some embodiments, a catheteris advanced through a cardiovascular system, such as described above, tothe target site. The catheter may be passed transluminally to theextravascular space or may create a virtual space between the vascularmedia and adventitia of the vessel. In some embodiments, the catheter,once positioned at the desired location is activated to selectivelymodulate or disrupt the target nerve or nerves. The selective disruptionmay be accomplished or performed through chemo-disruption, such assupplying any type of nerve destroying agent, including, but not limitedto, neurotoxins or other drugs detrimental to nerve viability. In someembodiments, selective disruption is performed through energy-induceddisruption, such as thermal or light ablation (e.g., radiofrequencyablation, ultrasound ablation, or laser ablation). In one embodiment, acamera or other visualization device (e.g., fiberoptic scope) isdisposed on a distal end of the catheter to ensure that nerves aretargeted and not surrounding tissue. If a target location is adjacentthe branch between the common hepatic artery and the proper hepaticartery, a less acute catheter bend may be required due to the angulationbetween the bifurcation of the common hepatic artery and the properhepatic artery. In some embodiments, the catheter comprises a side port,opening or window, thereby allowing for delivery of fluid or energy todenervate or ablate nerves with the longitudinal axis of the catheteraligned parallel or substantially parallel to the target vessel portion.In some embodiments, the catheter or probe is inserted percutaneouslyand advanced to the target location for extravascular delivery of energyor fluid.

C. Energy-Based Neuromodulation

1. Radiofrequency

In some embodiments, a catheter system comprises an ablation devicecoupled to a pulse-generating device. For example, the ablation devicemay be an ablation catheter. The ablation catheter may have a proximalend and a distal end. In some embodiments, the distal end of theablation catheter comprises one or more electrodes. The one or moreelectrodes can be positioned on an external surface of the ablationcatheter or can extend out of the distal end of the ablation catheter.In some embodiments, the electrodes comprise one or more bipolarelectrode pairs. In some embodiments, the electrodes comprise one ormore active electrodes and one or more return electrodes that cooperateto form electrode pairs. In some embodiments, one or more electrodes aremonopolar electrodes. In some embodiments, the distal end of theablation catheter comprises at least one bipolar electrode pair and atleast one monopolar electrode. One or more electrically conductive wiresmay connect one or more electrodes located at the distal end of theablation catheter to the pulse-generating device. In some embodiments,multiple electrodes can extend from the ablation catheter on multiplewires to provide multiple energy delivery locations or points within avessel (e.g., a hepatic artery).

In some embodiments, the pulse-generating device delivers electrical(e.g., radiofrequency (RF)) signals or pulses to the electrodes locatedat or near the distal end of the ablation catheter. The electrodes maybe positioned to deliver RF energy in the direction of sympathetic nervefibers in the hepatic plexus to cause ablation due to thermal energy. Insome embodiments, the electrodes are positioned on top of reflectivelayers or coatings to facilitate directivity of the RF energy away fromthe ablation catheter. In some embodiments, the electrodes are curved orflat. The electrodes can be dry electrodes or wet electrodes. In someembodiments, the catheter system comprises one or more probes with oneor more electrodes. For example, a first probe can include an activeelectrode and a second probe can include a return electrode. In someembodiments, the distal ends of the one or more probes are flexible. Theablation catheter can comprise a flexible distal end. Variable regionsof flexibility or stiffness are provided in some embodiments.

In one embodiment, a pair of bipolar electrodes is disposed at alocation that is substantially tangential to the inner lumen of thehepatic artery, each individual electrode having an arc length of 20degrees, with an inter-electrode spacing of 10 degrees. The edges of thetwo electrodes may have radii sufficient to reduce currentconcentrations. In some embodiments, the two electrodes are coated witha thin layer of non-conductive material to reduce current concentrationssuch that energy is delivered to target tissue via capacitive coupling.The arc length and spacing of the bipolar electrodes may be varied toalter the shape of the energy delivery zones and thermal lesions createdby the delivery of energy from the electrodes.

In some embodiments, peripheral active or grounding conductors are usedto shape an electric field. In one embodiment, a grounding needle ispositioned perivascularly to direct ablative current towards nerveswithin the perivascular space. In a non-invasive embodiment toaccomplish the same effect, high ion content material is infused intothe portal vein. In another embodiment, a shaping electrode ispositioned within the portal vein using percutaneous techniques such asemployed in transjugular intrahepatic portosystemic (TIPS) techniques.In one embodiment, a second shaping electrode is positioned in thebiliary tree endoscopically.

In some embodiments, a plurality of electrodes are spaced apartlongitudinally with respect to a center axis of the ablation catheter(e.g., along the length of the ablation catheter). In some embodiments,a plurality of electrodes are spaced apart radially around acircumference of the distal end of the ablation catheter. In someembodiments, a plurality of electrodes are spaced apart bothlongitudinally along a longitudinal axis of the ablation catheter andradially around a circumference of the ablation catheter from eachother. In various embodiments, the electrodes are positioned in variousother patterns (e.g., spiral patterns, checkered patterns, zig-zagpatterns, linear patterns, randomized patterns).

One or more electrodes can be positioned so as to be in contact with theinner walls (e.g., intima) of the blood vessel (e.g., common hepaticartery or proper hepatic artery) at one or more target ablation sitesadjacent the autonomic nerves to be disrupted or modulated, therebyproviding intravascular energy delivery. In some embodiments, theelectrodes are coupled to expandable and collapsible structures (e.g.,self-expandable or mechanically expandable) to facilitate contact withan inner vessel wall. The expandable structures can comprise coils,springs, prongs, tines, scaffolds, wires, stents, balloons, and/or thelike. The expandable electrodes can be deployed from the distal end ofthe catheter or from the external circumferential surface of thecatheter. The catheter can also include insulation layers adjacent tothe electrodes or active cooling elements. In some embodiments, coolingelements are not required. In some embodiments, the electrodes can beneedle electrodes configured to penetrate through a wall of a bloodvessel (e.g., a hepatic artery) to deliver energy extravascularly todisrupt sympathetic nerve fibers (e.g., the hepatic plexus). Forexample, the catheter can employ an intra-to-extravascular approachusing expandable needle electrodes having piercing elements. Theelectrodes can be disposable or reusable.

In some embodiments, the ablation catheter includes electrodes having asurface area of about 2 to about 5 mm², 5 to about 20 mm², about 7.5 toabout 17.5 mm², about 10 to about 15 mm², overlapping ranges thereof,less than about 5 mm², greater than about 20 mm², 4 mm², or about 12.5mm². In some embodiments, the ablation catheter relies only on directblood cooling. In some embodiments, the surface area of the electrodesis a function of the cooling available to reduce thrombus formation andendothelial wall damage. In some embodiments, lower temperature coolingis provided. In some embodiments, higher surface areas are used, therebyincreasing the amount of energy delivered to the perivascular space,including surface areas of about 5 to about 120 mm², about 40 to about110 mm², about 50 to about 100 mm², about 60 to about 90 mm², about 70to about 80 mm², overlapping ranges thereof, less than 5 mm², or greaterthan 120 mm². In some embodiments, the electrodes comprise stainlesssteel, copper, platinum, gold, nickel, nickel-plated steel, magnesium,or any other suitably conductive material. In some embodiments, positivetemperature coefficient (PTC) composite polymers having an inverse andhighly non-linear relationship between conductivity and temperature areused. In some embodiments, PTC electrodes (such as the PTC electrodesdescribed in U.S. Pat. No. 7,327,951, which is hereby incorporatedherein by reference) are used to control the temperature of RF energydelivered to the target tissue. For example, PTC electrodes may providehigh conductivity at temperatures below 60° C. and substantially lowerconductivity at temperatures above 60° C., thereby limiting the effectof energy delivery to tissue above 60° C.

FIG. 10 illustrates a self-repairing ablation catheter 1000. Theself-repairing ablation catheter 1000 comprises a catheter body 1005, aneedle electrode 1010, and a vascular wall plug 1015. In one embodiment,the needle electrode 1010 is placed at or near the distal end of thecatheter body 1005 and used to heat tissue (which may result in nerveablation). The vascular wall plug 1015 may be placed around the needleelectrode 1010 such that when the needle electrode 1010 is pushed intoor through the vascular wall, the vascular wall plug 1015 is pushed intoor through the vascular wall as well. Upon retracting the self-repairingablation catheter 1000, the needle electrode 1010 fully retracts in someembodiments, leaving the vascular wall plug 1015 behind, and therebyplugging or occluding the hole left by the needle electrode 1010.

In embodiments used to modulate (e.g., ablate) extravascularly, thevascular wall plug 1015 may comprise a hydrogel jacket or coatingdisposed on the needle electrode 1010. In some embodiments, the vascularwall plug 1015 is glued or otherwise adhered or fixed in a frangiblemanner at its distal end to the needle electrode 1010, yet may besufficiently thin so it does not prevent smooth passage of the needleelectrode 1010 as it is advanced into the perivascular space. In someembodiments, once the proximal end of the vascular wall plug 1015 passesout of the guiding lumen, it cannot be pulled proximally. Therefore,upon ablation completion, removal of the needle electrode 1010 from theperivascular space places the hydrogel jacket in compression in the holemade by the needle electrode 1010 in the vessel wall, thereby forming aplug which prevents or reduces the likelihood of vessel leakage orrupture. In some embodiments, the vascular wall plug 1015 is be made ofa hydrogel that swells when exposed to tissues, such as polyvinylalcohol, or a thrombogenic material, such as those employed duringinterventional radiology procedures to coil off non-target vessels.

FIG. 11 illustrates an embodiment of a hydrogel-coated electrodecatheter 1100. The hydrogel-coated electrode catheter 1100 includes acatheter body 1105, an ablation electrode 1110, and a hydrogel coating1115. In one embodiment, the ablation electrode 1110 is attached to thedistal end of the catheter body 1105 and the hydrogel coating 1115 coatsthe electrode 1110.

In some embodiments, the hydrogel coating 1115 is apreviously-desiccated hydrogel. Upon insertion into the target anatomy,the hydrogel coating 1115 on the ablation electrode 1110 may absorbwater from the surrounding tissues and blood. Ions drawn in from theblood (or included a priori in the hydrogel coating 1115) may impartconductive properties to the hydrogel coating 1115, thereby permittingdelivery of energy to tissue. In accordance with several embodiments,the hydrogel-coated electrode catheter 1100 requires less cooling duringablation, as the hydrogel coating resists desiccation. A smallercatheter size may also be used, as construction requirements and numberof components may be reduced. In some embodiments, the electrodeimpedance replicates native tissue impedance for better impedancematching. In some embodiments, temperature measurements at the surfaceof the hydrogel-coated electrode are possible.

In some embodiments, a balloon catheter comprises a catheter body and adistal balloon. The catheter body comprises a lumen configured tocontinuously infuse saline or other fluid into the balloon. The distalballoon comprises one or more hydrogel portions spaced around thecircumference of the distal balloon. In one embodiment, if saline isused, any water that vaporizes from the surface of the distal balloon isreplenished by diffusion from the balloon lumen, thereby preventing freesaline to travel into the vessel interface and reducing any undesiredeffects of saline infusion.

In accordance with several embodiments, the branches of the forksbetween the common hepatic artery, the proper hepatic artery and thegastroduodenal artery are advantageously simultaneously or sequentiallytargeted (e.g., with RF energy) because sympathetic nerves supplying theliver and pancreas are generally tightly adhered to or within the wallsof these arteries. Forks between other arteries or vessels may similarlybe simultaneously or sequentially be targeted (e.g., with RF energy). Insome embodiments, coiled electrodes opposing the artery walls are used.

FIG. 12A illustrates an embodiment of a single ablation coil 1200device. The single ablation coil device 1400 may be inserted into targetvasculature and activated to ablate the nerves within or surrounding thevasculature. To ablate a vascular fork, it may be necessary to insertthe single ablation coil 1200 into one branch of the fork (e.g., properhepatic artery branch) and ablate that branch, then insert the singleablation coil 1200 into the other branch of the fork (e.g.,gastroduodenal artery branch) and ablate that branch.

FIG. 12B illustrates a forked ablation coil device 1250. The forkedablation coil device 1250 comprises two ablation coils, a first ablationcoil 1255 and a second ablation coil 1260. In accordance with severalembodiments, the forked ablation coil device 1250 allows an entirevascular fork to be ablated simultaneously. In operation, the forkedablation coil device 1250 may be inserted to the target vasculature byoverlapping the first ablation coil 1255 and the second ablation coil1260 (effectively creating a single double helix coil). Once the targetfork is reached, the first ablation coil 1255 and the second ablationcoil 1260 may be separated and the first ablation coil 1255 insertedinto a first branch of the target fork and the second ablation coil 1260inserted into a second branch of the target fork. The branches of thetarget vessel fork (and the nerves within or surrounding the vessels ofthe fork branches) may then be simultaneously ablated.

In some embodiments, the coiled electrodes (e.g., ablation coil device1200 or forked ablation coil device 1250) are created out of a memorymaterial, such as nitinol or any other shape memory material. In someembodiments, energy may be delivered by the one or more coiledelectrodes in a manner so as not to cause nerve ablation (temporary orpermanent). In some embodiments, the thermal dose delivered may modulatenerves without causing ablation. The ablation coils may be delivered byone or more catheters. The ablation coils may be coupled to a cathetersuch that the ablation coils may be removed or repositioned followingablation of a target location. Balloon electrodes or other ablationelements may be used instead of ablation coils. In some embodiments, asingle balloon with multiple electrodes may be used instead of thecoiled electrodes. A portion of the balloon with an electrode may bepositioned in each of the branches. In other embodiments, each of thebranches may be occluded with an occlusion member and fluid may beinfused to create a wet electrode effect for ablation.

In some embodiments, energy is delivered between two ablation elementspositioned to span a vessel bifurcation in a bipolar manner, therebyconcentrating delivery of energy and denervation between the ablationelements in a bifurcation region where a higher density of nerve fibersmay exist.

FIGS. 13A-13C illustrate embodiments of balloon ablation catheters. FIG.13A illustrates an embodiment of a single balloon ablation catheter1300, FIG. 13B illustrates an embodiment of a forked double balloonablation catheter 1325, and FIG. 13C illustrates an embodiment of aforked balloon ablation catheter 1375.

The single balloon ablation catheter 1300 of FIG. 13A comprises anelectrode balloon 1305 having at least one electrode 1310 (e.g., oneelectrode, two electrodes, three electrodes, four electrodes, five toten electrodes, ten to twenty electrodes, or more than twentyelectrodes). The electrode patterns and configurations shown in FIGS.13A-13C illustrate various embodiments of electrode patterns andconfigurations; however, other patterns and configurations may be usedas desired or required. In some embodiments, a high dielectric constantmaterial may be used in the place of at least one electrode. The singleballoon ablation catheter 1300 may be inserted into target vasculatureand then inflated and used to ablate the vasculature (and thereby ablatethe nerves within or surrounding the vessel). To ablate a vascular fork,it may be necessary to insert the single balloon ablation catheter 1300into one branch of the fork and ablate that branch, then retract thesingle balloon ablation catheter 1300 from that branch and insert thesingle balloon ablation catheter 1300 into the other branch of the forkand ablate that branch.

The forked two balloon ablation catheter 1325 of FIG. 13B includes afirst electrode balloon 1330 and a second electrode balloon 1335. Thefirst electrode balloon 1330 includes at least a first electrode 1340,and the second electrode balloon 1330 includes at least a secondelectrode 1345. In several embodiments, the forked two balloon ablationcatheter 1325 allows an entire vascular fork (e.g., all branches) to beablated simultaneously. In operation, the forked two balloon ablationcatheter 1325 is inserted into the vasculature and advanced to thetarget fork. Once the target fork is reached, the left electrode balloon1330 and the right electrode balloon 1335 may be inflated and the leftelectrode balloon 1330 inserted into the left branch of the target forkand the right electrode balloon 1335 inserted into the right branch ofthe target fork (or vice versa). The target fork may then besimultaneously ablated. As discussed above, the first balloon and thesecond balloon can comprise a plurality of electrodes, or in someembodiments, at least one of the electrodes is replaced with a highdielectric constant material. The one or more electrodes may beindividually connected to a pulse generator. By selectively and/orsequentially activating one or more electrode pair simultaneously,energy delivery to the surrounding tissue can be uniquely directedtoward target anatomy with respect to balloon position. For example,referring now to FIG. 13C, energy could be directed between electrode1390A and electrode 1390B in order to create a focused lesion within thevessel wall, or between electrode 1390C and 1390D to focus energydelivery at the vessel bifurcation.

The forked balloon ablation catheter 1375 of FIG. 13C includes a singleballoon which has a left fork 1380 and a right fork 1385 with at leastone balloon electrode 1390. In some embodiments the forked balloonablation catheter 1375 comprises at least one balloon electrode for eachballoon fork. The electrodes can be spaced and distributed along theballoon to facilitate positioning of at least one balloon electrode ineach branch of the target fork. The forked balloon ablation catheter1375 operates in the same manner as the forked double balloon ablationcatheter 1325; however, it may advantageously allow for more effectiveablation of the crotch of the vascular fork. In some embodiments, theballoon of the forked balloon ablation catheter 1375 is substantiallythe shape of the target fork or is configured to conform to the shape ofthe target fork. In some embodiments, the forked balloon ablationcatheter 1375 is configured to be used in vessels having forks withthree or more branches (such as the fork between the common hepaticartery, proper hepatic artery and the gastroduodenal artery). In someembodiments, each of the branches of the vessel fork may be occludedwith an occlusion member and fluid may be infused to form a wetelectrode for ablation.

An electrode balloon may be used to ablate (or otherwise modulate)target vasculature. In some embodiments, the electrode balloon isinserted via a catheter and inflated such that the balloon is in contactwith substantially all of the fork intimal walls. In some embodiments,the electrode balloon is substantially oval. A two-step approach may beused to ablate the entire surface of the fork: first, the balloon can beput in place in one branch of the fork (e.g., the proper hepatic arterybranch), inflated, and then used to ablate; second, the balloon can beretracted and then advanced into the other fork (e.g., thegastroduodenal artery branch), inflated, and then used to ablate. Insome embodiments, the electrode balloon comprises ablation electrodes onan external surface in sufficient density that simultaneous ablation ofthe entire intimal wall in contact with the electrode balloon ispossible. In some embodiments, the ablation electrodes on the surface ofthe electrode balloon are arranged in a predetermined pattern. In someembodiments, the ablation electrodes on the surface of the electrodeballoon are activated simultaneously. In some embodiments, the ablationelectrodes on the surface of the electrode balloon are individuallyaddressable (e.g., actuatable), thereby allowing selective areas to beablated as desired. In some embodiments, at least one electrode on theelectrode balloon is an ablation electrode and at least one electrode onthe electrode balloon is a sensing electrode (used for example to senseimpedance, temperature, etc.).

In some embodiments, the electrode balloon comprises a proximalelectrode and a distal electrode configured to be individuallyactuatable and configured to be used in a stimulation mode, ablationmode, and/or sensing mode. The proximal electrode and distal electrodemay be positioned in two different branches (e.g., the proximalelectrode in the proper hepatic artery and the distal electrode in thegastroduodenal artery). The electrode balloon may be deployed from aguide catheter positioned in the common hepatic artery. In oneembodiment, the proximal electrode is stimulated and the distalelectrode is sensed and if the correct territory is identified (e.g.,nerve fibers emanating to the proper hepatic artery but not thegastroduodenal artery), then the proximal electrode may be activated forablation. The electrode balloon may be used to map and selectivelyablate various vessel portions.

In some embodiments, a round electrode balloon may be used toselectively ablate only a select area. In some embodiments, the roundelectrode balloon has approximately the same electrode properties asdescribed above, including electrode density, and the presence of atleast one ablation electrode. In some embodiments, the round electrodeballoon comprises at least one sensor electrode.

In some embodiments, a dielectric ablating balloon is used. Thedielectric ablating balloon may have the same shape characteristics asdo the other electrode balloon embodiments described herein. In someembodiments, the dielectric ablating balloon comprises at least onepiece of a high conductivity material on its outer surface. In someembodiments, use of the dielectric ablating balloon comprises advancingthe dielectric ablating balloon into position in the target vesselthrough methods described herein and inflating the dielectric ablatingballoon so that its outer surface is proximate to the intimal walls ofthe target vessel. In some embodiments, a microwave generator is thenplaced near the surface of the body of the subject and microwaves aredirected from the microwave generator toward the dielectric ablatingballoon within the subject such that the microwaves interact with the atleast one piece of a high conductivity material to create heat and suchthat the heat created thermally ablates the region (e.g., vessel wallsurface) proximate to the at least one high permittivity material. Insome embodiments, the dielectric ablating balloon comprises a pluralityof (e.g., two, three, four or more than four) pieces or portions of highconductivity material on its outer surface.

In some embodiments, lower power and longer timed ablations may be usedfor ablation procedures involving occlusion within the hepatic arteriesthan in other arteries. Such treatment may be uniquely possible becauseof the liver's dual source blood supply (as described above). Balloonablation of the hepatic artery may employ full occlusion for asubstantial period of time, not previously possible or not previouslyattempted in other locations for safety reasons (e.g., to avoidpotential stroke due to ischemia). In some embodiments, balloons may beinflated and used for ablation in the range of about 1 to about 10minutes, about 10 minutes to about 20 minutes, about 20 minutes to about60 minutes, about 15 minutes to about 45 minutes, about 10 minutes toabout 40 minutes, about 15 minutes, about 20 minutes, about 25 minutes,about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes,about 50 minutes, about 55 minutes, about 60 minutes. Longer ablationtimes may have several advantages in accordance with severalembodiments. First, longer exposure times mean that lower treatmenttemperatures may be used because tissue and nerve death is a function ofboth temperature and time. In some embodiments, temperatures are used inthe ranges of about 30° C. to about 80° C., about 40° C. to about 70°C., or about 50° C. to about 60° C. In one embodiment, temperaturesgreater than 45° C. and less than 60° C. are used.

In some embodiments, the arterial lumen may be simultaneously protectedby infusing a low temperature coolant through the balloon cavity(thereby keeping the intima cool) while focusing RF energy and thermalheating at the level of the adventitia (where the target nerves arelocated). Second, balloon occlusion may facilitate improved contact andcontact pressure between the electrodes disposed on the outside of theballoon and the arterial wall. Third, balloon occlusion may compress thetissues of the arterial wall and thereby reduce the distance from theelectrode(s) to the target nerves, which improves the efficiency ofthermal energy delivery to the target nerves. Fourth, lesscontrast/imaging agent may be required by using a balloon catheterbecause an occluding device is reliably and accurately positioned (andmaintains that position once in place), and serves as a reliable markerof device and therapy placement. Additionally, when a balloon engagesthe vascular wall, heating of the blood is avoided entirely (becauseenergy is transferred directly from the electrode(s) to the vessel wallwithout directly contacting the blood), thereby reducing the risk ofvapor bubble formation or thrombosis (e.g., clot formation).

Balloon ablation catheter systems may be advantageous for denervatingnerves surrounding the hepatic artery branches may be advantageous inthat the hepatic artery can be occluded by one or more balloons and thencoolant can be circulated in the region of the ablation (e.g., through alumen of a balloon). In various embodiments, balloon ablation cathetersadvantageously facilitate both higher power net energy through largerelectrode surface area (enabled, for example, by large electrode sizesthat can be included on a balloon) and increased deposition time (whichmay be permitted by the ability to occlude flow to the hepatic arteryfor longer periods of time). In some embodiments, the risk of damage tothe endothelial wall is mitigated by the flow of coolant even with anincrease in energy density through higher power. Accordingly, higherpower energy delivery (e.g., about 40 to 50% higher power) may be usedthan denervation systems used for denervation of other vessels or organswithout risk of damage to the endothelial region of the hepatic arterydue to maintained less than hyperthermic temperatures up to 1 mm fromthe lumen of the hepatic artery.

In some embodiments, an actively-cooled balloon catheter is used toablate target vasculature. A pump sufficient to deliver high flowcoolant to the cooling element may be used to facilitate the activecooling. In several embodiments, the range of drive pressures to deliveran appropriate flow rate (e.g., between about 100 and 500 mL/min) ofcoolant into a 4 to 6 Fr balloon catheter to maintain an appropriatetemperature is between about 25 and about 150 psi. The flow rate may beadjusted on the basis of the actual temperature inside the balloon. Insome embodiments, the desired coolant temperature in the balloon isbetween about 5° C. and about 10° C. In some embodiments, thermocouplesare included inside the balloon to constantly monitor the coolanttemperature. The pump output may be increased or decreased based on thedifference between the desired temperature and the actual temperature ofthe coolant.

The hepatic artery anatomy is generally more tortuous and variable thananatomies of other vessels in other areas. Maintaining good contact ofelectrodes or other energy delivery elements in the tortuous hepaticartery anatomy can be difficult and may require the use of differentcatheter devices than existing catheter devices for nerve ablation.FIGS. 14A and 14B illustrate an embodiment of a low-profile ablationcatheter 1400 that may advantageously facilitate contact of electrodesor other energy delivery elements with the inner walls of arteries ofthe tortuous hepatic vascular anatomy. The low-profile ablation catheter1400 comprises an inner electrode member 1410 and an outer sheath 1415.The inner electrode member 1410 may comprise a reversibly deflectable,pre-shaped cylindrical shaft comprising resilient (e.g., shape memory)material and at least one electrode 1420. In one embodiment, the outersheath 1415 comprises a guide catheter having a lumen. The innerelectrode member 1410 may be configured to be delivered within the lumenof the outer sheath 1415 and to be translatable relative to the outersheath 1415 such that the inner electrode member 1410 may be advancedout of a distal end of the outer sheath 1415 and retracted back in. Inone embodiment, the inner electrode member 1410 assumes a generallydeflected (e.g., off-axis) configuration when advanced out of the distalend of the outer sheath 1415, as shown in FIG. 14B. In thisunconstrained state, the distal end of the inner electrode member 1410deviates from a longitudinal axis defined by the proximal portion of theelectrode. When the inner electrode member 1410 is retracted within theouter sheath 1415, the inner electrode member 1410 is resilientlydeformed to assume a substantially straight shape defined by thesubstantially straight shape of the lumen of the outer sheath 1415, asshown in FIG. 14A. In some embodiments, when the inner electrode member1410 is advanced out of the distal end of the outer sheath 1415, thedistal end portion of the inner electrode member 1410 deflects tocontact a vessel wall (e.g., arterial wall). The shape of the distal endof the inner electrode member 1410 in the unconstrained state may bepre-formed to ensure contact with the vessel wall.

In some embodiments, the outer sheath 1415 has a diameter of less thanabout 4 mm, less than about 3 mm, less than about 2 mm, or less thanabout 1 mm. In some embodiments, the inner electrode member 1410comprises a shaft formed, at least partly, of memory material such as anickel titanium alloy material. The inner electrode member 1410 may havean outer cross-sectional dimension that is substantially equal to theoutside diameter of the outer sheath 1415 or may have an outercross-sectional dimension that is smaller or larger than the outsidediameter of the outer sheath 1415. In some embodiments, when the innerelectrode member 1410 is slid out of the outer sheath 1415 past apre-formed step 1425 at or near its distal end, the step 1425 at or nearthe distal end places the surface of the distal end of the innerelectrode member 1410 away from the natural axis of the outer sheath1415. In some embodiments, the step 1425 near the distal end of theinner electrode member 1410 places the surface of the inner electrodemember 1410 between about the same plane as the outer surface of theouter sheath 1415 and about double the diameter from the center of theouter sheath 1415 to the outer surface of the outer sheath 1415.

In some embodiments, the magnitude of the off-axis deflection created inthe step 1425 near the distal end is tailored to satisfy varyinganatomic requirements (e.g., larger step near the distal end for largerblood vessels and smaller step near the distal end for smaller bloodvessels). In some embodiments, the inner electrode member 1410 isinterchangeable and may be replaced with a different inner electrodemember with different size parameters. The different sizes of innerelectrode members or electrode members with different pre-formed shapesmay be provided in a kit and an appropriate inner electrode member maybe selected after evaluating patient anatomy (for example, by CT,fluoroscopy, or ultrasound imaging methods). In some embodiments, theinner electrode member 1410 is rotated within the catheter body

In some embodiments, the at least one electrode 1420 of the innerelectrode member 1410 comprises one or more monopolar, bipolar ormultipolar electrodes (the addition of additional pre-shaped electrodesmay enable bipolar and multi-polar RF energy delivery). Any combinationof electrodes may be incorporated into the design of the inner electrodemember 1410 to create a catheter with any desired properties.

In some embodiments, the shaft of the inner electrode member 1410comprises an insulation member to prevent heat transfer away from orelectrically insulate portions of the inner electrode member 1410. Insome embodiments, the insulation member is a tubing, coating or heatshrink comprised of polyamide, polytetrafluoroethylene,polyetheretherketone, polyethylene, or any other high dielectricmaterial. The insulation member may comprise one or more openings toexpose portions of the distal end portion of the inner electrode member1410. In some embodiments, the insulation member is used to definespecific electrode geometries by selective removal of the insulationmember in whatever geometry is desired. In other embodiments, the innerelectrode member 1410 comprises a shape memory polymer or shape-biasedpolymer with one or more electrode leads disposed therein. In oneembodiment, the low-profile ablation catheter comprises a cathetercoextruded with a shape memory electrode spine, where the extrudedcatheter provides electrical insulation. In one embodiment, the at leastone electrode 1420 comprises a spherical electrode. In one embodiment,the distal end of the inner electrode shaft comprises a series ofelectrodes.

In some embodiments, the low-profile ablation catheter 1400 comprises aradial window or slot in a side portion near the distal end of theablation catheter. In one embodiment, the distal end of the innerelectrode member 1410 is configured to be deployed out of the radialwindow or slot. In one embodiment, the lumen of the ablation catheter1400 comprises a ramp leading up to the radial window or slot to directthe distal end of the inner electrode member out of the radial window orslot.

In accordance with several embodiments, the low-profile ablationcatheter 1400 advantageously provides a device that comprises a lowprofile (e.g., small outer cross-sectional dimension) and uses the samemechanism to actuate the electrode deflection as well as the electrodeitself, thereby reducing the number of distinct components. The innerelectrode 1410 of the low-profile ablation catheter may alsoadvantageously be at least partially deployed to facilitate navigationby providing a variety of tip curvature options for “hooking” vascularbranches or navigating tortuous vessels during catheter insertion. Inaccordance with several embodiments, the low-profile ablation catheter1400 advantageously facilitates solid and continuous contact with thevessel wall, thereby allowing for substantially constant voltage tomaintain a desired electrode tip temperature.

FIG. 15 illustrates various embodiments of distal tip electrode andguide wire shapes 1500. The distal tip electrode and guide wire shapes1500 may include an “L” shaped tip 1505, a “J” shaped tip 1510, a“shepherds crook”-shaped tip 1515, a “hook” shaped tip 1520, a “line”shaped tip 1525, a “key” shaped tip 1530, a “circle” shaped tip 1535, a“square hook” shaped tip 1540, or a “step” shaped hook 1545. Aspiral-shaped tip (such as shown in FIG. 12A) may also be used. In oneembodiment, a lasso-shaped tip is used. The lasso-shaped tip may have asimilar configuration to the “circle” shaped tip 1535 but with the“circle”- or “lasso”-shaped tip portion being oriented substantiallyperpendicular to the straight line portion. The various shapesillustrated in FIG. 15 may advantageously be selected from and used inconjunction with the low-profile ablation catheter 1400 or othercatheter devices to facilitate contact of electrodes or other energydelivery elements with the inner walls of arteries of the tortuoushepatic vascular anatomy (e.g., based on the particular vascular anatomyof the subject being treated or the particular vessels being treated).Any of the shapes 1500 shown in FIG. 15 may comprise a plurality ofelectrodes arranged in different patterns.

In some embodiments, the distal tip electrode itself, or a guide wire,may be partially or fully extended from an insertion catheter, to aid innavigation, thereby providing for a variety of tip curvature options for“hooking” vascular branches during catheter insertion. In someembodiments, shape-memory electrodes may be interchangeable by aclinician-user. For example, the clinician may select the mostappropriate shape conformation for the patient's unique anatomy from akit of different shaped devices, rather than being bound to a singledevice conformation or configuration. The various shaped tips mayadvantageously be selected to optimize the ability for the one or moreelectrodes or energy delivery elements to contact the target vessel dueto the tortuosity and variability of the vascular anatomy at and/orsurrounding the target vessel. The electrode assembly may also include asensing element, such as a thermal sensing element (thermistor orthermocouple) to permit measurement of tissue temperatures and energydelivery during the treatment. The sensing element may provide feedbackregarding confirmation of denervation or blocking of nerve conduction.

In accordance with several embodiments, once a particular shape isselected, forces (F) can be applied to the proximal end of the electrodeto adjust the contact force F′ against a vessel wall. In someembodiments, the degree of strain of the electrode distal portion isproportional to the force applied to the vessel wall. Radiopaque markersmay be placed along the length of the inner electrode 1410 and therelative angle Φ between lines drawn between two of the radiopaquemarkers can be designed such that F′=f(Φ(F)). A clinician may thenadjust the force on the proximal end of the electrode to achieve thedesired contact force.

In some embodiments, a catheter having an outer diameter substantiallymatching the target vessel's inner diameter is used, thereby minimizingmechanical and footprint requirements for precise targeting. A cathetermay be selected from a kit of catheters having various outside diameterdimensions based on a measured inner diameter of the target vessel. Insome embodiments, the outside diameter of a catheter can be modifiedusing spacers provided in a procedure kit. The catheter may be advancedthrough the patient's vasculature (the inner diameter of which maydecrease as the target location nears). Once the catheter is advanced tothe target vessel location, it may then advantageously engage the vesselwall with substantially uniform contact pressure about itscircumference. In some embodiments, because application of energy to theentire circumference of the vessel is undesirable (due to the risk ofstenosis,) any of the designs herein disclosed that employ selectiveelectrode placement or electrode “windows” are used, thereby allowingthe delivery of energy in discrete locations about the vessel wall.

FIGS. 16A and 16B illustrate an embodiment of a windowed ablationcatheter 1600. The windowed ablation catheter 1600 comprises a catheterbody 1605, an inner sleeve 1610 having a first window 1620 and at leastone ablation electrode 1630 and an outer sleeve 1615 having a secondwindow 1625. FIG. 16A shows a view of the distal end of the windowedablation catheter 1600 and FIG. 16B shows a detailed cut-away view ofthe distal end of the windowed ablation catheter 1600.

In some embodiments, the ablation electrode 1630 is disposed within alumen of the inner sleeve 1610. The inner sleeve 1610 is rotatablyreceived within the outer sleeve 1615 such that the outer sleeve 1615 isrotatable about the inner sleeve 1610. Energy can be delivered by thecatheter by aligning the second window 1625 of the outer sleeve 1615with the first window 1620 of the inner sleeve 1610 by rotating theinner sleeve 1610 with respect to the outer sleeve 1615, or vice-versa.In one embodiment, the inner sleeve 1610 comprises a dielectric coveringto provide insulation.

In some embodiments, when the first window 1620 of the inner sleeve 1610and the second window 1625 of the outer sleeve 1615 overlap, theablating electrode 1630 is exposed to the outside of the outer sleeve1615 (which may be placed against the wall of the target vessel). In oneembodiment, energy only reaches the wall of the target vessel when thefirst window 1620 and the second window 1625 overlap, or are at leastpartially aligned. The degree of overlap may be controlled by therotation or translation of the inner sleeve 1610 relative to the outersleeve 1615. In one embodiment, the catheter is inserted by a user, theinner sleeve 1610 is turned based on user control, and the outer sleeve1615 is turned based on user control, thereby allowing selectiveapplication of energy generated by the at least one ablation electrodeto substantially any portion of the target vessel.

In some embodiments, the inner sleeve 1610 comprises multiple openingsspaced along the length of the inner sleeve 1610 at different locations.For example, the inner sleeve 1610 may have openings spaced linearlyalong the axis of the inner sleeve 1610 and openings rotated about theaxis of the inner sleeve 1610. In one embodiment, the openings of theinner sleeve 1610 define a spiral pattern. As shown in FIG. 16B, theexternal surface of the inner sleeve 1610 and the internal surface ofthe outer sleeve 1615 may be threaded such that the inner sleeve 1610 istranslated with respect to the outer sleeve 1615 by rotation of theouter sleeve 1615 relative to the inner sleeve 1610. In someembodiments, relative rotation of the outer sleeve 1615 with respect tothe inner sleeve 1610 serves to both translate and rotate window 1625 ofthe outer sleeve 1615, sequentially exposing vascular tissue to theablation electrode 1635 through each of the openings of the inner sleeve1610. In accordance with several embodiments, a windowed ablationcatheter as described herein may facilitate creation of a spiral lesionalong a length of the vessel wall. By selectively creating openings inthe inner sleeve 1610, and rotating the outer sleeve 1615 with respectto the inner sleeve 1610, substantially any pattern of ablation along ahelical path may be created.

To improve ablation catheter-vascular wall contact and thereby improvetreatment efficacy, some embodiments include a window on the distal tipof the ablation catheter, or incorporated into one or more of theelectrode windows, to provide suction (or vacuum pressure). The suctionprovided to the lumen wall places the artery in direct contact with thedevice to thereby achieve more efficient and less damaging ablation.

FIG. 17 is an embodiment of a balloon-based volume ablation system 1700,which can be used, for example, in the celiac, common hepatic, andproper hepatic arteries. In the illustrated embodiment, theballoon-based volume ablation system 1700 comprises a plurality ofocclusive balloons 1725, a plurality of balloon guide wires 1730, acatheter 1750, and an electrode 1740. FIG. 17 also illustrates theabdominal aorta 1705, the celiac artery 1706, the common hepatic artery1707, the splenic artery 1708, the proper hepatic artery 1709, the righthepatic artery 1710, and the left hepatic artery 1711 as an example of atarget treatment site. In operation, the balloon-based volume ablationsystem 1700 may be inserted to the target treatment site through theabdominal aorta 1705 and into the celiac artery 1706. Individualocclusive balloons 1725 may then be advanced into subsequent vessels,such as the splenic artery 1708, the right hepatic artery 1710 and theleft hepatic artery 1711. When the appropriate occlusive balloons 1725have been placed such that they define the desired volume of vasculatureto be ablated, the occlusive balloons 1725 may be inflated, therebyoccluding the vessels in which they have been placed. In one embodiment,the target volume is then filled with saline and the electrode 1740 isactivated to deliver electrical energy to heat the entire target volumesimultaneously. The electrode 1740 may be configured to deliversufficient energy to the target volume to ablate all or at least aportion of the nerves of the vessels within the target treatment site.Upon completion, the occlusive balloons 1725 may be deflated and theentire balloon-based volume ablation system 1700 may be retracted.

In some embodiments, it may be advantageous to simultaneously ablate aregion of nerves innervating a portion of all, or a subset of all,arteries arising from the celiac artery (such as the left gastricartery, the splenic artery, the right gastric artery, the gastroduodenalartery, and the hepatic artery). In some embodiments, ablation isachieved by using balloon catheters or other occlusion members deployedfrom a guide catheter within the celiac artery or abdominal aorta toblock off or occlude portions of vessels not to be ablated (the targetvolume may be adjusted by inflating balloons or placing occlusionmembers upstream and downstream of the desired volume, thereby creatinga discrete volume), filling the target volume with saline solutionthrough a guide catheter, and applying RF or other energy to the salineto thereby ablate the tissues surrounding the target volume in a mannerthat maintains vessel patency with hydraulic pressure while alsoproviding for direct cooling of the endothelial surfaces of the vesselsthrough circulation of chilled saline. In some embodiments, thedescribed “saline electrode” system is used to pressurize the targetarteries with saline. The contact pressure of the saline electrodeagainst the arterial walls can be assessed by measurement of thearterial diameter on angiography and utilizing the pre-definedrelationship between arterial diameter and fluid pressure or by usingone or more pressure sensors, which in one embodiment, are included as acomponent of the saline electrode system. The saline electrode systemmay advantageously facilitate omnidirectional delivery of energy.

In some embodiments, hypertonic (e.g., hyperosmolar) saline is used inthe ablation of the target volume. Using hypertonic saline may cause“loading” of the endothelial cells with ions, effectively increasingtheir conductivity. The loading of the endothelial cells with ions mayhave one or more of the following effects: decreasing ion friction inthe endothelial lining (and other cells affected along the osmosisgradient, such as those in the media); reducing the heat deposited inthe endothelial cell locations; preventing significant thermal damage tothe endothelial cells; and increasing current density as a result of theincreased conductivity in the region near the electrode, which mayadvantageously increase the efficiency of heating deeper in the vesselwall where the target nerves may be located.

In various embodiments, capacitive coupling or resistive heatingcatheter devices are used to deliver thermal energy. In one embodiment,a capacitive coupling catheter device comprises a balloon comprising abipolar electrode pair arranged in a capacitive coupling configurationwith an insulation layer between the two electrodes. In one embodiment,the insulation layer coats the two electrodes. In one embodiment, theballoon comprises a non-conductive balloon filled with saline that iscapacitively coupled to the target tissue through the dielectric layerformed by the substantially non-conductive balloon membrane. Thecapacitive coupling catheter device may advantageously not requiredirect electrode contact with the target tissue, thereby reducingcurrent density levels and edge effects required by other devices.Capacitive coupling devices or methods similar to those described inU.S. Pat. No. 5,295,038, incorporated herein by reference, may be used.A return electrode path may also be provided.

In one embodiment, a resistive heating energy delivery cathetercomprises a balloon catheter having a resistive heating element disposedthereon. For example, the balloon catheter may comprise spiral resistiveheater that wraps around the balloon. Instead of inducing RF currents inthe vascular tissue, DC or AC/RF currents can be used to generate heatin the balloon catheter itself and the heat can be transmitted to thesurrounding vascular tissue (e.g., hepatic arterial tissue) byconduction.

In some embodiments, an RF energy delivery system delivers RF energywaves of varying duration. In some embodiments, the RF energy deliverysystem varies the amplitude of the RF energy. In other embodiments, theRF energy delivery system delivers a plurality of RF wave pulses. Forexample, the RF energy delivery system may deliver a sequence of RFpulses. In some embodiments, the RF energy delivery system varies thefrequency of RF energy. In other embodiments, the RF energy deliverysystem varies any one or more parameters of the RF energy, including,but not limited to, duration, amplitude, frequency, and total number ofpulses or pulse widths. For example, the RF energy delivery system candeliver RF energy selected to most effectively modulate (e.g., ablate orotherwise disrupt) sympathetic nerve fibers in the hepatic plexus. Insome embodiments, the frequency of the RF energy is maintained at aconstant or substantially constant level.

In some embodiments, the frequency of the RF energy is between about 50kHz and about 20 MHz, between about 100 kHz and about 2.5 MHz, betweenabout 400 kHz and about 1 MHz, between about 50 kHz and about 5 MHz,between about 100 kHz and about 10 MHz, between about 500 kHz and about15 MHz, less than 50 kHz, greater than 20 MHz, between about 3 kHz andabout 300 GHz, or overlapping ranges thereof. Non-RF frequencies mayalso be used. For example, the frequency can range from about 100 Hz toabout 3 kHz. In some embodiments, the amplitude of the voltage appliedis between about 1 volt and 1000 volts, between about 5 volts and about500 volts, between about 10 volts and about 200 volts, between about 20volts and about 100 volts, between about 1 volt and about 10 volts,between about 5 volts and about 20 volts, between about 1 volt and about50 volts, between about 15 volts and 25 volts, between about 20 voltsand about 75 volts, between about 50 volts and about 100 volts, betweenabout 100 volts and about 500 volts, between about 200 volts and about750 volts, between about 500 volts and about 1000 volts, less than 1volt, greater than 1000 volts, or overlapping ranges thereof.

In some embodiments, the current of the RF energy ranges from about 0.5mA to about 500 mA, from about 1 mA to about 100 mA, from about 10 mA toabout 50 mA, from about 50 mA to about 150 mA, from about 100 mA toabout 300 mA, from about 250 mA to about 400 mA, from about 300 to about500 mA, or overlapping ranges thereof. The current density of theapplied RF energy can have a current density between about 0.01 mA/cm²and about 100 mA/cm², between about 0.1 mA/cm² and about 50 mA/cm²,between about 0.2 mA/cm² and about 10 mA/cm², between about 0.3 mA/cm²and about 5 mA/cm², less than about 0.01 mA/cm², greater than about 100mA/cm², or overlapping ranges thereof. In some embodiments, the poweroutput of the RF generator ranges between about 0.1 mW and about 100 W,between about 1 mW and 100 mW, between about 1 W and 10 W, between about10 W and 50 W, between about 25 W and about 75 W, between about 50 W andabout 90 W, between about 75 W and about 100 W, or overlapping rangesthereof. In some embodiments, the total RF energy dose delivered at thetarget location (e.g., at an inner vessel wall, to the media of thevessel, to the adventitia of the vessel, or to the target nerves withinor adhered to the vessel wall) is between about 100 J and about 2000 J,between about 150 J and about 500 J, between about 300 J and about 800J, between about 500 J and about 1000 J, between about 800 J and about1200 J, between about 1000 J and about 1500 J, and overlapping rangesthereof. In some embodiments, the impedance ranges from about 10 ohms toabout 600 ohms, from about 100 ohms to about 300 ohms, from about 50ohms to about 200 ohms, from about 200 ohms to about 500 ohms, fromabout 300 ohms to about 600 ohms, and overlapping ranges thereof.

The RF energy can be pulsed or continuous. The voltage, current density,frequencies, treatment duration, power, and/or other treatmentparameters can vary depending on whether continuous or pulsed signalsare used. For example, the voltage or current amplitudes may besignificantly increased for pulsed RF energy. The duty cycle for thepulsed signals can range from about 0.0001% to about 100%, from about0.001% to about 100%, from about 0.01% to about 100%, from about 0.1% toabout 100%, from about 1% to about 10%, from about 5% to about 15%, fromabout 10% to about 50%, from about 20% to about 60% from about 25% toabout 75%, from about 50% to about 80%, from about 75% to about 100%, oroverlapping ranges thereof. The pulse durations or widths of the pulsescan vary. For example, in some embodiments, the pulse durations canrange from about 10 microseconds to about 1 millisecond; however, pulsedurations less than 10 microseconds or greater than 1 millisecond can beused as desired and/or required. In accordance with some embodiments,the use of pulsed energy may facilitate reduced temperatures, reducedtreatment times, reduced cooling requirements, and/or increased powerlevels without risk of increasing temperature or causing endothelialdamage due to heating.

The treatment time durations can range from 1 second to 1 hour, from 5seconds to 30 minutes, from 10 seconds to 10 minutes, from 30 seconds to30 minutes, from 1 minute to 20 minutes, from 1 minute to 3 minutes,from 2 to four minutes, from 5 minutes to 10 minutes, from 10 minutes to40 minutes, from 30 seconds to 90 seconds, from 5 seconds to 50 seconds,from 60 seconds to 120 seconds, overlapping ranges thereof, less than 1second, greater than 1 hour, about 120 seconds, or overlapping rangesthereof. The duration may vary depending on various treatment parameters(e.g., amplitude, current density, proximity, continuous or pulsed, typeof nerve, size of nerve). In some embodiments, the RF or otherelectrical energy is controlled such that delivery of the energy heatsthe target nerves or surrounding tissue in the range of about 50 toabout 90 degrees Celsius (e.g., 60 to 75 degrees, 50 to 80 degrees, 70to 90 degrees, or overlapping ranges thereof). In some embodiments, thetemperature can be less than 50 or greater than 90 degrees Celsius. Theelectrode tip energy may range from 37 to 100 degrees Celsius. In someembodiments, RF ablation thermal lesion sizes range from about 0 toabout 3 cm (e.g., between 1 and 5 mm, between 2 and 4 mm, between 5 and10 mm, between 15 and 20 mm, between 20 and 30 mm, overlapping rangesthereof, about 2 mm, about 3 mm) or within one to ten (e.g., one tothree, two to four, three to five, four to eight, five to ten) mediathickness differences from a vessel lumen (for example, research hasshown that nerves surrounding the common hepatic artery and otherbranches of the hepatic artery are generally within this range). Inseveral embodiments, the media thickness of the vessel (e.g., hepaticartery) ranges from about 0.1 cm to about 0.25 cm. In some anatomies, atleast a substantial portion of nerve fibers of the hepatic arterybranches are localized within 0.5 mm to 1 mm from the lumen wall suchthat modulation (e.g., denervation) using an endovascular approach iseffective with reduced power or energy dose requirements.

In some embodiments, an RF ablation catheter is used to perform RFablation of sympathetic nerve fibers in the hepatic plexus at one ormore locations. For example, the RF ablation catheter may performablation in a circumferential or radial pattern to ablate sympatheticnerve fibers in the hepatic plexus at one or more locations (e.g., one,two, three, four, five, six, seven, eight, nine, ten, six to eight, fourto eight, more than ten locations). In other embodiments, thesympathetic nerve fibers in the hepatic plexus are ablated at one ormore points by performing RF ablation at a plurality of points that arelinearly spaced along a vessel length. For example, RF ablation may beperformed at one or more points linearly spaced along a length of theproper hepatic artery to ablate sympathetic nerve fibers in the hepaticplexus. In some embodiments, RF ablation is performed at one or morelocations in any pattern to cause ablation of sympathetic nerve fibersin the hepatic plexus as desired and/or required (e.g., a spiral patternor a series of linear patterns that may or may not intersect). Theablation patterns can comprise continuous patterns or intermittentpatterns. In accordance with various embodiments, the RF ablation doesnot cause any lasting damage to the vascular wall because heat at thewall is dissipated by flowing blood, by cooling provided external to thebody, or by increased cooling provided by adjacent organs and tissuestructures (e.g., portal vein cooling and/or infusion), thereby creatinga gradient with increasing temperature across the intimal and mediallayers to the adventitia where the nerves travel. The adventitia is theexternal layer of the arterial wall, with the media being the middlelayer and the intima being the inner layer. The intima comprises a layerof endothelial cells supported by a layer of connective tissue. Themedia is the thickest of the three vessel layers and comprises smoothmuscle and elastic tissue. The adventitia comprises fibrous connectivetissue.

In some embodiments, the energy output from the RF energy source may bemodulated using constant temperature mode. Constant temperature modeturns the energy source on when a lower temperature threshold is reachedand turns the energy source off when an upper temperature threshold isreached (similar to a thermostat). In some embodiments, an ablationcatheter system using constant temperature mode requires feedback,which, in one embodiment, is provided by a temperature sensor. In someembodiments, the ablation catheter system comprises a temperature sensorthat communicates with energy source (e.g., RF generator). In some ofthese embodiments, the energy source begins to deliver energy (e.g.,turn on) when the temperature sensor registers that the temperature hasdropped below a certain lower threshold level, and the energy sourceterminates energy delivery (e.g., turns off) when the temperature sensorregisters that the temperature has exceeded a predetermined upperthreshold level.

In some embodiments, the energy output from an energy delivery systemmay be modulated using a parameter other than temperature, such astissue impedance. Tissue impedance may increase as tissue temperatureincreases. Impedance mode may be configured to turn the energy source onwhen a lower impedance threshold is reached and turn the energy sourceoff when an upper impedance threshold is reached (in the same fashion asthe constant temperature mode responds to increases and decreases intemperature). An energy delivery system using constant impedance modemay include some form of feedback mechanism, which, in one embodiment,is provided by an impedance sensor. In some embodiments, impedance iscalculated by measuring voltage and current and dividing voltage by thecurrent.

In some embodiments, a catheter-based energy delivery system comprises afirst catheter with a first electrode and a second catheter with asecond electrode. The first catheter is inserted within a target vessel(e.g., the common hepatic artery) and used to deliver energy to modulatenerves within the target vessel. The second catheter may be insertedwithin an adjacent vessel and the impedance can be measured between thetwo electrodes. For example, if the first catheter is inserted withinthe hepatic arteries, the second catheter can be inserted within thebile duct or the portal vein. In some embodiments, a second electrode isplaced on the skin of the subject and the impedance is measured betweenthe second electrode and an electrode of the catheter-based energydelivery system. In some embodiments, the second electrode may bepositioned in other locations that are configured to provide asubstantially accurate measurement of the impedance of the targettissues.

In some embodiments, the impedance measurement is communicated to theenergy source (e.g., pulse generator). In some embodiments, the energysource begins to generate a pulse (i.e., turns on) when the impedanceregisters that the impedance has dropped below a certain lower thresholdlevel, and the energy source terminates the pulse (i.e., turns off) whenthe impedance registers that the impedance has exceeded a predeterminedupper threshold level.

In some embodiments, the energy output of the energy delivery system ismodulated by time. In such embodiments, the energy source of the energydelivery system delivers energy for a predetermined amount of time andthen terminates energy delivery for a predetermined amount of time. Thecycle may repeat for a desired overall duration of treatment. In someembodiments, the predetermined amount of time for which energy isdelivered and the predetermined amount of time for which energy deliveryis terminated are empirically optimized lengths of time. In accordancewith several embodiments, controlling energy delivery according toimpedance and reducing energy delivery when impedance approaches athreshold level (or alternatively, modulating energy in timeirrespective of impedance levels) advantageously provides for thermalenergy to be focused at locations peripheral to the vessel lumen. Forexample, when the energy pulse is terminated, the vessel lumen may coolrapidly due to convective heat loss to blood, thereby protecting theendothelial cells from thermal damage. In some embodiments, the heat inthe peripheral tissues (e.g., where the targeted nerves are located)dissipates more slowly via thermal conduction. In some embodiments,successive pulses tend to cause preferential heating of the peripheral(e.g., nerve) tissue. In accordance with several embodiments, when theimpedance of tissue rises due to vaporization, electrical conductivitydrops precipitously, thereby effectively preventing further delivery ofenergy to target tissues. In some embodiments, by terminating energypulses before tissue impedance rises to this level (e.g., by impedancemonitoring or time modulation), this deleterious effect may be avoided.In accordance with several embodiments, char formation is a consequenceof tissue vaporization and carbonization, resulting from rapid increasesin impedance, electrical arcing, and thrombus formation. By preventingimpedance rises, charring of tissue may be avoided.

In some embodiments, total energy delivery is monitored by calculatingthe time integral of power output (which may be previously correlated toablation characteristics) to track the progress of the therapy. In someembodiments, the relationship between temperature, time, and electricalfield is monitored to obtain an estimate of the temperature field withinthe tissue surrounding the ablation electrode using the Arrheniusrelationship. In some embodiments, a known thermal input is provided tothe ablation electrode, on demand, in order to provide known initialconditions for assessing the surrounding tissue response. In someembodiments, a portion of the ablation region is temporarily cooled, andthe resultant temperature is decreased. For example, for an endovascularablation that has been in progress for a period of time, it may beexpected that there is some elevated temperature distribution within thetissue. If a clinician wants to assess the progress of the therapy at agiven time (e.g., t₀), the energy delivery can be interrupted, andcooled saline or gas can be rapidly circulated through the electrode toachieve a predetermined electrode temperature within a short period oftime (e.g., about 1 second). In some embodiments, the resultingtemperature rise (e.g., over about 5 seconds) measured at the electrodesurface is then a representation of the total energy of the surroundingtissue. This process can be repeated through the procedure to trackprogress.

In some embodiments, a parameter, such as temperature, infraredradiation, or microwave radiation can be monitored to assess themagnitude of energy delivered to tissue, and thus estimate the degree ofneuromodulation induced. Both the magnitude of thermal radiation(temperature), infrared radiation, and/or microwave radiation may beindicative of the amount of energy contained within a bodily tissue. Insome embodiments, the magnitude is expected to decrease following thecompletion of the ablation as the tissue cools back towards bodytemperature, and the rate of this decrease, measured at a specific point(e.g., at the vessel lumen surface) can be used to assess the size ofthe ablation (e.g., slower decreases may correspond to larger ablationsizes). Any of the embodiments described herein may be used individuallyor in combination to indicate the actual size of the tissue lesion zone.

In various embodiments, the rate change of various treatment parameters(e.g., impedance, electrode temperature, tissue temperature, power,current, voltage, time, and/or energy is monitored substantially in realtime and displayed on a user interface. Treatment parameter data may bestored on a data store for later reporting and/or analysis. In someembodiments, an energy delivery system receives inputs transduced fromphysiologic signals such as blood glucose levels, norepinephrine levels,or other physiological parameters indicative of the status of theprogress of treatment.

Other methods of observing the tissue ablation zone and the surroundinganatomy may include prior, concomitant, or subsequent imagingintravascularly by modalities including but not limited to:intravascular ultrasound, optical coherence tomography, confocalmicroscopy, infrared spectroscopy, ultraviolet spectroscopy, Ramanspectroscopy, and microwave thermometry. All such imaging modalities mayadvantageously be adapted to the hepatic artery because of its uniquetolerance to low flow. In some embodiments, ultrasound elastography isadvantageously used for imaging. Ultrasound elastography may show areasof localized tissue stiffness resulting from the denaturing of collagenproteins during thermal ablation (ablated regions tend to stiffencompared to the native tissue); for example, stiff regions maycorrespond to ablated regions. Intravascular ultrasound may be used forexample, to detect or monitor the presence and depth of ablationlesions. For example, if the lesions are in the range of 2 to 6 mm fromthe lumen wall, the clinician may be confident that the target nerveswere destroyed as a result of thermal coagulation. Extravascularultrasound imaging may also be used.

2. Ultrasound

In some embodiments, an energy delivery system delivers ultrasonicenergy to modulate (e.g., ablate, stimulate) sympathetic nerve fibers inthe hepatic plexus. For example, the energy delivery system can employfocused ultrasonic energy such as high-intensity focused ultrasonic(HIFU) energy or low-intensity focused ultrasonic (LIFU) energy toablate sympathetic nerve fibers. In some embodiments, the energydelivery system includes an ablation catheter connected to one or moreultrasound transducers. For example, the ultrasound transducer(s) candeliver ultrasonic energy to one or more ablation sites to ablatesympathetic nerve fibers in the hepatic plexus. The ultrasonic energycan be controlled by dosing, pulsing, or frequency selection. In someembodiments, HIFU energy can advantageously be focused at a distantpoint to reduce potential disturbance of the tissue of the blood vessel(e.g., the intima and the media layers) or surrounding tissues. HIFUenergy can advantageously reduce the precision required for positioningof the ablation catheter. The one or more ultrasound transducers can berefocused during treatment to increase the number of treatment sites orto adjust the depth of treatment. In some embodiments, the use of HIFUenergy can result in increased concentrations of heat for a shorterduration and can simultaneously focus energy at multiple focal points,thereby reducing the total time required to administer theneuromodulation procedure.

In some embodiments, the energy delivery system comprises a focusedultrasound (e.g., HIFU) ablation catheter and an acoustic frequencygenerator. The ablation catheter can be steerable from outside of thesubject using a remote mechanism. The distal end of the ablationcatheter can be flexible to allow for deflection or rotational freedomabout an axis of the catheter shaft to facilitate positioning within ahepatic or other artery. For example, the one or more ultrasoundtransducers, which may be single element or multiple elementtransducers, against the intima of the artery or spaced at a distancefrom the intimal layer. In some embodiments, the ablation cathetercomprises focusing (e.g., parabolic) mirrors or other reflectors,gas-filled or liquid-filled balloons, and/or other structural focusingelements to facilitate delivery of the ultrasonic energy. The one ormore transducers can be cylindrical, rectangular, elliptical, or anyother shape. The ablation catheter can comprise sensors and controlcircuits to monitor temperature and prevent overheating or to acquireother data corresponding to the one or more ultrasound transducers, thevessel wall and/or the blood flowing across the ultrasound transducer.In some embodiments, the sensors provide feedback to control delivery ofthe ultrasonic energy. In some embodiments, the ultrasound energy iscontrolled such that delivery of the ultrasound energy heats thearterial tissue in the range of about 40 to about 90° C. (e.g., 40° C.to 60° C., 60° C. to 75° C., 65° C. to 80° C., 60° C. to 90° C., oroverlapping ranges thereof. In some embodiments, the temperature can beless than 40° C. or greater than 90° C.

The frequencies used to ablate the sympathetic nerves can vary based onexpected attenuation, the containment of the beam both laterally andaxially, treatment depths, type of nerve, and/or other parameters. Insome embodiments, the frequencies used range from about 20 kHz to about20 MHz, from about 500 kHz to about 10 MHz, from about 1 MHz to about 5MHz, from about 2 MHz to about 6 MHz, from about 3 MHz to about 8 MHz,less than 20 kHz, greater than 20 MHz or overlapping ranges thereof.However, other frequencies can be used without limiting the scope of thedisclosure. In some embodiments, the HIFU catheter can also transmitfrequencies that can be used for imaging purposes or for confirmation ofsuccessful ablation or denervation purposes. In some embodiments, theHIFU catheter delivers energy having parameters such that cavitationdoes not occur. The average ultrasound intensity for ablation ofsympathetic nerve fibers in the hepatic plexus, celiac plexus or othersympathetic nerve fibers can range from about 1 W/cm² to about 10kW/cm², from about 500 W/cm² to about 5 kW/cm², from about 2 W/cm² toabout 8 kW/cm², from about 1 kW/cm² to about 10 kW/cm², from about 25W/cm² to about 200 W/cm², from about 200 W/cm² to about 1 MW/cm², lessthan 1 W/cm², greater than 10 kW/cm², or overlapping ranges thereof.Power levels may range from about 25 W/cm² to about 1 MW/cm² (dependingon the intensity of the ultrasound energy and/or other parameters). Theultrasound energy can be continuous or pulsed. The power levels orenergy density levels used for pulsed ultrasound energy may be higherthan the power levels used for continuous ultrasound energy.

The treatment time for each target ablation site can range from about 5seconds to about 120 seconds, from about 10 seconds to about 60 seconds,from about 20 seconds to about 80 seconds, from about 30 seconds toabout 90 seconds, less than 10 seconds, greater than 120 seconds, oneminute to fifteen minutes, ten minutes to one hour, or overlappingranges thereof. In accordance with several embodiments, the parametersused are selected to disable, block, cease or otherwise disruptconduction of sympathetic nerves of the hepatic plexus for at leastseveral months while creating minimal damage of the arterial walls orsurrounding tissues or organs.

3. Lasers

In several embodiments, lasers may be used to modulate (e.g., ablate)sympathetic nerve activity of the hepatic plexus or other nervesinnervating the liver. Although lasers are not generally used forarterial nerve ablation in other arteries, the wall thickness of thehepatic arteries is substantially less than the thickness of otherarterial structures, thereby rendering laser energy delivery possible.In some embodiments, one or more lasers are used to ablate nerveslocated within about 2 mm of the intimal surface, within about 1.5 mm ofthe intimal surface, within about 1 mm of the intimal surface, or withinabout 0.5 mm of the intimal surface of a hepatic artery. In someembodiments, chromophore staining of sympathetic fibers is performed toselectively enhance sympathetic nerve absorption of laser energy. Insome embodiments, balloons are used to stretch the hepatic artery,thereby thinning the arterial wall and decreasing the depth from theintimal surface to the sympathetic nerve fibers, and thereby improvingthe delivery of the laser energy.

Other forms of optical or light energy may also be used. The lightsource may include an LED light source, an electroluminescent lightsource, an incandescent light source, a fluorescent light source, a gaslaser, a chemical laser, a dye laser, a metal-vapor laser, a solid statelaser, a semiconductor laser, a vertical cavity surface emitting laser,or other light source. The wavelength of the optical or laser energy mayrange from about 300 nm to about 2000 nm, from about 500 nm to about1100 nm, from about 600 nm to about 1000 nm, from about 800 nm to about1200 nm, from about 1000 nm to about 1600 nm, or overlapping rangesthereof.

4. Externally-Initiated

In accordance with various embodiments, energy delivery is initiatedfrom a source external to the subject (e.g., extracorporeal activation).FIG. 18 illustrates an embodiment of a microwave-based energy deliverysystem 1800. The microwave-based energy delivery system 1800 comprisesan ablation catheter 1805 and a microwave generating device 1820. Insome embodiments, other energy sources may also be delivered externally.

In some embodiments, the ablation catheter 1805 comprises a highconductivity probe 1810 disposed at its distal end. In operation, theablation catheter 1805 may be inserted into a target vessel andpositioned such that the high conductivity probe 1810 is proximate tothe site targeted for ablation. The microwave generating device 1820 islocated outside a subject's body and positioned such that focusedmicrowaves 1825 are delivered towards the target vessel and the highconductivity probe 1810. In several embodiments, when the deliveredfocused microwaves 1825 contact the high conductivity probe 1810, theyinduce eddy currents within the high conductivity probe 1810, therebyheating the high conductivity probe 1810. The thermal energy 1815generated from the heating of the high conductivity probe can heat thetarget tissue through conductive heat transfer. In some embodiments, thethermal energy 1815 generated is sufficient to ablate nerves within ordisposed on the target tissue (e.g., vessel wall). In variousembodiments, the high conductivity probe 1810 has a conductivity greaterthan 10^3 Siemens/meter.

FIG. 19 illustrates an embodiment of an induction-based energy deliverycatheter system 1900. In the illustrated embodiment, the induction-basedenergy delivery system 1900 comprises a catheter 1905, an induction coil1910, an external inductor power circuit 1950, an inductor 1960, aresistor 1970, and a capacitor 1980. In one embodiment, the inductioncoil 1910 is disposed at the distal end of the catheter 1905. Inoperation, the induction coil 1910 may act as an inductor to receiveenergy from the external inductive power circuit 1950. In someembodiments, the external inductive power circuit 1950 is positionedsuch that the inductor 1960 is adjacent the induction coil 1910 within asufficient induction range. In some embodiments, current is deliveredthrough the external inductive power circuit 1950, thereby causingcurrent to flow in the induction coil 1910 and delivering subsequentablative energy to surrounding tissues. In one embodiment, an inductioncoil is used in combination with any of the windowed catheter devicesdescribed herein (such as the windowed catheter devices described inconnection with FIGS. 16A and 16B). For example, the induction coil maybe placed within a lumen of a catheter or sleeve having one or morewindows configured to permit the selective delivery of energy to thetarget tissue.

In some embodiments, one or more synthetic emboli may be inserted withina target vessel and implanted or lodged therein (at least temporarily).The synthetic emboli may advantageously be sized to match the anatomy ofthe target vessel (e.g., based on angiography of the target location andvessel diameter). The synthetic emboli may be selected based on ameasured or estimated dimension of the target vessel. In one embodiment,an energy delivery catheter is coupled to the one or more syntheticemboli inserted within a target vessel to deliver energy. In someembodiments, energy is delivered transcutaneously to the syntheticemboli using inductive coupling as described in connection with FIG. 21,thereby eliminating the need for an energy delivery catheter. Thesynthetic emboli may comprise an induction coil and a plurality ofelectrodes embedded within an insulating support structure comprised ofhigh dielectric material. After appropriate energy has been delivered tomodulate nerves associated with the target vessel, the one or moreemboli may be removed.

In several embodiments of the invention, the energy-based deliverysystems comprise cooling systems that are used to, for example, reducethermal damage to regions surrounding the target area. For example,cooling may lower (or maintain) the temperature of tissue at below aparticular threshold temperature (e.g., at or between 40 to 50 degreesCelsius), thereby preventing or reducing cell necrosis. Cooling balloonsor other expandable cooling members are used in some embodiments. In oneembodiment, ablation electrodes are positioned on a balloon, which isexpanded using cooling fluid. In some embodiments, cooling fluid iscirculated through a delivery system (e.g., a catheter system). In someembodiments, cooling fluid (such as pre-cooled saline) may be delivered(e.g., ejected) from a catheter device in the treatment region. Infurther embodiments, cooling fluid is continuously or intermittentlycirculated internally within the catheter device to cool the endothelialwall in the absence of sufficient blood flow.

D. Steam/Hot Water Neuromodulation

FIG. 20 illustrates an embodiment of a steam ablation catheter 2000. Inthe illustrated embodiment, the steam ablation catheter 2000 comprises awater channel 2005, a steam generating head 2010, and a steam outlet2015. In operation, water may be forced through the water channel 2005and caused to enter the steam generating head 2010. In one embodiment,the steam generating head 2010 converts the water into steam, whichexits the steam ablation catheter 2000 through the steam outlet 2015.

In some embodiments, steam is used to ablate or denervate the targetanatomy (e.g., hepatic arteries and nerves associated therewith). Inaccordance with several embodiments, water is forced through theablation catheter 2000 and out through the steam generating head 2010(which converts the water into steam) and the steam is directed to anablation target. The steam ablation catheter 2000 may comprise one ormore window along the length of the catheter body.

FIG. 21 illustrates an embodiment of a hot fluid balloon ablationcatheter 2100. In the illustrated embodiment, the hot fluid balloonablation catheter 2100 comprises an inflatable balloon 2105. In someembodiments, the inflatable balloon 2105 is filled with a temperaturevariable fluid 2110. In accordance with several embodiments, hot wateris the temperature variable fluid 2110 used to fill the inflatableballoon 2105. The heat generated from the hot fluid within theinflatable balloon may be sufficient to ablate or denervate the targetanatomy (e.g., hepatic arteries and nerves associated therewith). Insome embodiments, the inflatable balloon 2105 is inserted to theablation site and inflated with scalding or boiling fluid (e.g., water),thereby heating tissue surrounding the inflatable balloon 2105sufficient to ablate or denervate the tissue. In some embodiments, thehot fluid within the balloon 2105 is within the temperature range ofabout 120° F. to about 212° F., from about 140° F. to about 212° F.,from about 160° F. to about 212° F., from about 180° F. to about 212°F., about 200° F. to about 212° F., or overlapping ranges thereof. Insome embodiments, the balloon ablation catheter 2100 comprises atemperature sensor and fluid (e.g., water) at different temperatures maybe inserted and withdrawn as treatment dictates. In some embodiments,the inflatable balloon 2105 is made out of polyurethane or any otherheat-resistant inflatable material.

E. Chemical Neuromodulation

In some embodiments, drugs are used alone or in combination with anothermodality to cause neuromodulation. Drugs include, but are not limitedto, muscarinic receptor agonists, anticholinesterase agents, nicotinicreceptor agonists, and nicotine receptor antagonists. Drugs thatdirectly affect neurotransmission synthesis, degradation, or reuptakeare used in some embodiments.

In some embodiments, drugs (either alone or in combination with energymodalities) can be used for neuromodulation. For example, a deliverycatheter may have one or more internal lumens. In some embodiments, oneor more internal lumens are in fluid communication with a proximalopening and with a distal opening of the delivery catheter. In someembodiments, at least one distal opening is located at the distal end ofthe delivery catheter. In some embodiments, at least one proximalopening is located at the proximal end of the delivery catheter. In someembodiments, the at least one proximal opening is in fluid communicationwith at least one reservoir.

In some embodiments, at least one reservoir is a drug reservoir thatholds drugs or therapeutic agents capable of modulating sympatheticnerve fibers in the hepatic plexus. In some embodiments, a separate drugreservoir is provided for each drug used with the delivery cathetersystem. In other embodiments, at least one drug reservoir may hold acombination of a plurality of drugs or therapeutic agents. Any drug thatis capable of modulating nerve signals may be used in accordance withthe embodiments disclosed herein. In some embodiments, neurotoxins(e.g., botulinum toxins) are delivered to the liver, pancreas, or othersurrounding organs or nerves associated therewith. In some embodiments,neurotoxins (e.g., botulinum toxins) are not delivered to the liver,pancreas, or other surrounding organs or nerves associated therewith.

In some embodiments, a delivery catheter system includes a deliverydevice that delivers one or more drugs to one or more target sites. Forexample, the delivery device may be a pump. Any pump, valve, or otherflow regulation member capable of delivering drugs through a cathetermay be used. In some embodiments, the pump delivers at least one drugfrom the at least one drug reservoir through the at least one internallumen of the catheter delivery system to the one or more target sites.

In some embodiments, the pump selects the drug dosage to be deliveredfrom the reservoir to the target site(s). For example, the pump canselectively vary the total amount of one or more drugs delivered asrequired for neuromodulation. In some embodiments, a plurality of drugsis delivered substantially simultaneously to the target site. In otherembodiments, a plurality of drugs is delivered in series. In otherembodiments, a plurality of drugs is delivered substantiallysimultaneously and at least one other drug is delivered either before orafter the plurality of drugs is delivered to the target site(s). Drugsor other agents may be used without delivery catheters in someembodiments. According to several embodiments, drugs may have aninhibitory or stimulatory effect.

In some embodiments, an ablation catheter system uses chemoablation toablate nerve fibers (e.g., sympathetic nerve fibers in the hepaticplexus). For example, the ablation catheter may have one or moreinternal lumens. In some embodiments, one or more internal lumens are influid communication with a proximal opening and with a distal opening.In some embodiments, at least one distal opening is located in thedistal end of an ablation catheter. In some embodiments, at least oneproximal opening is located in the proximal end of the ablationcatheter. In some embodiments, at least one proximal opening is in fluidcommunication with at least one reservoir.

In some embodiments, at least one reservoir holds and/or stores one ormore chemicals capable of disrupting (e.g., ablating, desensitizing,destroying) nerve fibers (e.g., sympathetic nerve fibers in the hepaticplexus). In some embodiments, a separate reservoir is provided for eachchemical used with the ablation catheter system. In other embodiments,at least one reservoir may hold any combination of chemicals. Anychemical that is capable of disrupting nerve signals may be used inaccordance with the embodiments disclosed herein. For example, one ormore chemicals or desiccants used may include phenol or alcohol,guanethidine, zinc sulfate, nanoparticles, radiation sources forbrachytherapy, neurostimulants (e.g., methamphetamine), and/or oxygenradicals (e.g., peroxide). However, any chemical that is capable ofablating sympathetic nerve fibers in the hepatic plexus may be used inaccordance with the embodiments disclosed herein. In some embodiments,chemoablation is carried out using a fluid delivery needle deliveredpercutaneously, laparascopically, or via an intravascular approach.

F. Cryomodulation

In some embodiments, the invention comprises cryotherapy orcryomodulation. In one embodiment, the ablation catheter system usescryoablation techniques for neuromodulation. In one embodiment,cryoablation is used to ablate sympathetic nerve fibers in the hepaticplexus. For example, the ablation catheter may have one or more internallumens. In some embodiments, one or more internal lumens are in fluidcommunication with a proximal opening. In some embodiments, at least oneproximal opening is located in the proximal end of the ablationcatheter. In some embodiments, at least one proximal opening is in fluidcommunication with at least one reservoir (e.g., a cryochamber). In someembodiments, the at least one reservoir holds one or more coolantsincluding but not limited to liquid nitrogen. The ablation catheter cancomprise a feed line for delivering coolant to a distal tip of theablation catheter and a return line for returning spent coolant to theat least one reservoir. The coolant may reach a temperature sufficientlylow to freeze and ablate sympathetic nerve fibers in the hepatic plexus.In some embodiments, the coolant can reach a temperature of less than 75degrees Celsius below zero, less than 80 degrees Celsius below zero,less than 90 degrees Celsius below zero, or less than 100 degreesCelsius below zero.

In some embodiments, the ablation catheter system includes a deliverydevice that controls delivery of one or more coolants through one ormore internal lumens to the target site(s). For example, the deliverydevice may be a pump. Any pump, valve or other flow regulation memberthat is capable of delivering coolants through a catheter may be used.In some embodiments, the pump delivers at least one coolant from atleast one reservoir, through at least one proximal opening of thecatheter body, through at least one internal lumen of the catheter body,and to the distal end of the ablation catheter (e.g., via a feed line orcoolant line).

In some embodiments, the target nerves may be irreversibly cooled usingan implantable Peltier cooling device. In some embodiments, animplantable cooling device is configured to be refilled with an inertgas that is injected at pressure into a reservoir within the implantabledevice and then released selectively in the vicinity of the targetnerves, cooling them in an adiabatic fashion, thereby slowing orterminating nerve conduction (either temporarily or permanently). Insome embodiments, local injections or infusion of ammonium chloride isused to induce a cooling reaction sufficient to alter or inhibit nerveconduction. In some embodiments, delivery of the coolant to the distalend of the ablation catheter, which may comprise one or more ablationelectrodes or a metal-wrapped cylindrical tip, causes denervation ofsympathetic nerve fibers in the hepatic plexus. For example, when theablation catheter is positioned in or near the proper hepatic artery orthe common hepatic artery, the temperature of the coolant may cause thetemperature of the surrounding area to decrease sufficiently todenervate sympathetic nerve fibers in the hepatic plexus. In someembodiments, cryoablation is performed using a cryocatheter.Cryoablation can alternatively be performed using one or more probesalone or in combination with a cryocatheter.

The treatment time for each target ablation site can range from about 5seconds to about 100 seconds, 5 minutes to about 30 minutes, from about10 minutes to about 20 minutes from about 5 minutes to about 15 minutes,from about 10 minutes to about 30 minutes, less than 5 seconds, greaterthan 30 minutes, or overlapping ranges thereof. In accordance withseveral embodiments, the parameters used are selected to disable, block,cease or otherwise disrupt conduction of, for example, sympatheticnerves of the hepatic plexus. The effects on conduction of the nervesmay be permanent or temporary. One, two, three, or more cooling cyclescan be used.

In some embodiments, any combination of drug delivery, chemoablation,and/or cryoablation is used for neuromodulation, and may be used incombination with an energy modality. In several embodiments, coolingsystems are provided in conjunction with energy delivery to, forexample, protect tissue adjacent the nerve fibers.

III. Image Guidance, Mapping and Selective Positioning

Image guidance techniques may be used in accordance with several of theembodiments disclosed herein. For example, a visualization element(e.g., a fiber optic scope) may be provided in combination with acatheter-based energy or fluid delivery system to aid in delivery andalignment of a neuromodulation catheter. In other embodiments,fluoroscopic, ultrasound, Doppler or other imaging is used to aid indelivery and alignment of the neuromodulation catheter. In someembodiments, radiopaque markers are located at the distal end of theneuromodulation catheter or at one or more locations along the length ofthe neuromodulation catheter. For example, for catheters havingelectrodes, at least one of the electrodes may comprise a radiopaquematerial. Computed tomography (CT), fluorescence, radiographic,thermography, Doppler, optical coherence tomography (OCT), intravascularultrasound (IVUS), and/or magnetic resonance (MR) imaging systems, withor without contrast agents or molecular imaging agents, can also be usedto provide image guidance of a neuromodulation catheter system. In someembodiments, the neuromodulation catheter comprises one or more lumensfor insertion of imaging, visualization, light delivery, aspiration orother devices.

In accordance with some embodiments, image or visualization techniquesand systems are used to provide confirmation of disruption (e.g.,ablation, destruction, severance, denervation) of the nerve fibers beingtargeted. In some embodiments, the neuromodulation catheter comprisesone or more sensors (e.g., sensor electrodes) that are used to provideconfirmation of disruption (e.g., ablation, destruction, severance,denervation) of communication of the nerve fibers being targeted.

In some embodiments, the sympathetic and parasympathetic nerves aremapped prior to modulation. In some embodiments, a sensor catheter isinserted within the lumen of the vessel near a target modulation area.The sensor catheter may comprise one sensor member or a plurality ofsensors distributed along the length of the catheter body. After thesensor catheter is in place, either the sympathetic nerves or theparasympathetic nerves may be stimulated. In some embodiments, thesensor catheter is configured to detect electrical activity. In someembodiments, when the sympathetic nerves are artificially stimulated andparasympathetic nerves are left static, the sensor catheter detectsincreased electrical activity and the data obtained from the sensorcatheter is used to map the sympathetic nervous geometry. In someembodiments, when the parasympathetic nerves are artificially stimulatedand sympathetic nerves are left static, the sensor catheter detectsincreased electrical activity and the data obtained from the sensorcatheter is used to map the parasympathetic nervous geometry. In someembodiments, mapping the nervous geometry using nervous stimulation andthe sensor catheter advantageously facilitates improved or more informedselection of the target area to modulate, leaving select nerves viablewhile selectively ablating and disrupting others. As an example of oneembodiment, to selectively ablate sympathetic nerves, the sympatheticnerves may be artificially stimulated while a sensor catheter, alreadyinserted, detects and maps areas of increased electrical activity. Todisrupt the sympathetic nerves, only the areas registering increasedelectrical activity may need to be ablated.

In one embodiment, a method of targeting sympathetic nerve fibersinvolves the use of electrophysiology mapping tools. While applyingcentral or peripheral nervous signals intended to increase sympatheticactivity (e.g., by administering noradrenaline or electricalstimulation), a sensing catheter may be used to map the geometry of thetarget vessel (e.g., hepatic artery) and highlight areas of increasedelectrical activity. An ablation catheter may then be introduced andactivated to ablate the mapped areas of increased electrical activity,as the areas of increased electrical activity are likely to beinnervated predominantly by sympathetic nerve fibers. In someembodiments, nerve injury monitoring (NIM) methods and devices are usedto provide feedback regarding device proximity to sympathetic nerveslocated perivascularly. In one embodiment, a NIM electrode is connectedlaparascopically or thorascopically to sympathetic ganglia.

In some embodiments, to selectively target the sympathetic nerves, localconductivity may be monitored around the perimeter of the hepaticartery. Locations corresponding to maximum impedance are likely tocorrespond to the location of the sympathetic nerve fibers, as they arefurthest away from the bile duct and portal vein, which course posteriorto the hepatic artery and which are highly conductive compared to othertissue surrounding the portal triad. In some methods, to selectivelydisrupt sympathetic nerves, locations with increased impedance areselectively modulated (e.g., ablated). In some embodiments, one or morereturn electrodes are placed in the portal vein and/or bile duct toenhance the impedance effects observed in sympathetic nervous tissues.In some embodiments, return electrodes are placed on areas of the skinperfused with large veins and having decreased fat and/or non-vasculartissues (such as the neck or wrist, etc.). The resistance between theportal vein and other veins may be very low because of the increasedelectrical conductivity of blood relative to other tissues. Therefore,the impedance effects may be enhanced because comparatively smallchanges in resistance between various positions on the hepatic arteryand the portal vein are likely to have a relatively large impact on theoverall resistance registered.

In some embodiments, the sympathetic nerves are targeted locationally.It may be observed in some subjects that sympathetic nerve fibers tendto run along a significant length of the proper hepatic artery while theparasympathetic nerve fibers tend to join towards the distal extent ofthe proper hepatic artery. In some embodiments, sympathetic nerves aretargeted by ablating the proper hepatic artery towards its proximalextent (e.g., generally halfway between the first branch of the celiacartery and the first branch of the common hepatic artery or about onecentimeter, about two centimeters, about three centimeters, about fourcentimeters, or about five centimeters beyond the proper hepatic arterybranch). Locational targeting may be advantageous because it can avoiddamage to critical structures such as the bile duct and portal vein,which generally approach the hepatic artery as it courses distallytowards the liver.

In some embodiments, neuromodulation location is selected by relation tothe vasculature's known branching structure (e.g., directly after agiven branch). In some embodiments, neuromodulation location is selectedby measurement (e.g., insertion of a certain number of centimeters intothe target vessel). Because the relevant nervous and vessel anatomy ishighly variable in humans, it may be more effective in some instances toselect neuromodulation location based on a position relative to thebranching anatomy, rather than based on a distance along the hepaticartery. In some subjects, nerve fiber density is qualitatively increasedat branching locations.

In some embodiments, a method for targeting sympathetic nerve fiberscomprises assessing the geometry of arterial structures distal of theceliac axis using angiography. In one embodiment, the method comprisescharacterizing the geometry into any number of common variations andthen selecting neuromodulation (e.g., ablation) locations based on theexpected course of the parasympathetic nerve fibers for a given arterialvariation. Because arterial length measurements can vary from subject tosubject, in some embodiments, this method for targeting sympatheticnerve fibers is performed independent of arterial length measurements.The method may be used for example, when it is desired to denervate orablate a region adjacent and proximal to the bifurcation of the commonhepatic artery into the gastroduodenal and proper hepatic arteries.

In the absence of nerve identification under direct observation, nervescan be identified based on their physiologic function. In someembodiments, mapping and subsequent modulation is performed usingglucose and norepinephrine (“NE”) levels. In some embodiments, glucoseand NE levels respond with fast time constants. Accordingly, a clinicianmay stimulate specific areas (e.g., in different directions orcircumferential clock positions or longitudinal positions) in a targetartery or other vessel, monitor the physiologic response, and thenmodulate (e.g., ablate) only in the locations that exhibited theundesired physiologic response. Sympathetic nerves tend to run towardsthe anterior portion of the hepatic artery, while the parasympatheticnerves tend to run towards the posterior portion of the hepatic artery.Therefore, one may choose a location not only anterior, but also (usingthe aforementioned glucose and NE level measurements) a specificlocation in the anterior region that demonstrated the strongestphysiologic response to stimulation (e.g., increase in glucose levelsdue to sympathetic stimulation). In some embodiments, stimulation with0.1 s-on, 4.9 s-off, 14 Hz, 0.3 ms, 4 mA pulsed RF energy is asympathetic activator and stimulation with 2 s-on, 3 s-off, 40 Hz, 0.3ms, 4 mA pulsed RF energy is a parasympathetic activator. However, otherparameters of RF energy or other energy types may be used.

In some embodiments, using electrical and/or positional selectivity, aclinician could apply a stimulation pulse or signal and monitor aphysiologic response. Some physiologic responses that may indicateefficacy of treatment include, but are not limited to, the following:blood glucose levels, blood and/or tissue NE levels, vascular muscletone, blood insulin levels, blood glucagon levels, blood C peptidelevels, blood pressure (systolic, diastolic, average), and heart rate.In some cases, blood glucose and tissue NE levels may be the mostaccurate and readily measured parameters. The physiologic responses maybe monitored or assessed by arterial or venous blood draws, nerveconduction studies, oral or rectal temperature readings, or percutaneousor surgical biopsy. In some embodiments, transjugular liver biopsies aretaken after each incremental ablation to measure the resultant reductionin tissue NE levels and treatment may be titrated or adjusted based onthe measured levels. For example, in order to measure tissue NE levelsin the liver, a biopsy catheter may be inserted by a TIPS approach orother jugular access to capture a sample of liver parenchyma. In someembodiments, the vein wall of the portal vein may safely be violated toobtain the biopsy, as the vein is surrounded by the liver parenchyma,thereby preventing blood loss.

In some embodiments, ablation is performed using an ablation catheterwith radiopaque indicators capable of indicating proper position whenviewed using fluoroscopic imaging. Due to the two-dimensional nature offluoroscopic imaging, device position can only be determined along asingle plane, providing a rectangular cross-section view of the targetvasculature. In order to overcome the difficulty of determining deviceposition along a vessel circumference without repositioning thefluoroscopic imaging system, rotational positioning indicators that arevisible using fluoroscopic imaging may advantageously be incorporated onan endovascular ablation device to indicate the circumferential positionof ablation components (e.g., electrodes) relative to the vesselanatomy.

In one embodiment, an ablation catheter having an ablation electrodecomprises three radiopaque indicators positioned along the longitudinalaxis of the ablation catheter. In one embodiment, the first radiopaqueindicator is positioned substantially adjacent to the electrode on thedevice axis; the second radiopaque indicator is positioned proximal tothe electrode on the device axis; and the third radiopaque indicator ispositioned off the device axis. In one embodiment, the third radiopaqueindicator is positioned between the first and second radiopaqueindicators. In embodiments with three radiopaque indicators, theablation electrode is configured to contact the vessel wall throughdeflection from the central axis of the catheter. In one embodiment,alignment of the first and second radiopaque indicators means that theablation electrode is located in a position spaced from, and directlyperpendicular to, the imaging plane (e.g., either anteriorly orposteriorly assuming a coronal imaging plane). In one embodiment, theposition of the third radiopaque indicator indicates theanterior-posterior orientation. For example, position of the thirdradiopaque indicator above, on, or below the line formed between thefirst and second radiopaque indicators may provide the remaininginformation necessary to allow the user to infer the position of theablation catheter.

IV. Alternative Catheter Delivery Methods

In addition to being delivered intravascularly through an artery, theneuromodulation systems described herein (e.g., ablation cathetersystems) can be delivered intravascularly through the venous system. Forexample, an ablation catheter system may be delivered through the portalvein. In other embodiments, an ablation catheter system is deliveredintravascularly through the inferior vena cava. Any other intravasculardelivery method or approach may be used to deliver neuromodulationsystems, e.g., for modulation of sympathetic nerve fibers in the hepaticplexus.

In some embodiments, the neuromodulation systems (e.g., cathetersystems) are delivered transluminally to modulate nerve fibers. Forexample, catheter systems may be delivered transluminally through thestomach. In other embodiments, the catheter systems are deliveredtransluminally through the duodenum, or transluminally through thebiliary tree via endoscopic retrograde cholangiopancreatography (ERCP).Any other transluminal or laparoscopic delivery method may be used todeliver the catheter systems according to embodiments described herein.

In some embodiments, the catheter systems are delivered percutaneouslyto the biliary tree to ablate sympathetic nerve fibers in the hepaticplexus. Any other minimally invasive delivery method may be used todeliver neuromodulation systems for modulation or disruption ofsympathetic nerve fibers in the hepatic plexus as desired and/orrequired.

In some embodiments, an open surgical procedure is used to modulatesympathetic nerve fibers in the hepatic plexus. Any open surgicalprocedure may be used to access the hepatic plexus. In conjunction withan open surgical procedure, any of the modalities described herein forneuromodulation may be used. For example, RF ablation, ultrasoundablation, HIFU ablation, ablation via drug delivery, chemoablation,cryoablation, ionizing energy delivery (such as X-ray, proton beam,gamma rays, electron beams, and alpha rays) or any combination thereofmay be used with an open surgical procedure. In one embodiment, nervefibers (e.g., in or around the hepatic plexus) are surgically cut inconjunction with an open surgical procedure in order to disruptsympathetic signaling, e.g., in the hepatic plexus.

In some embodiments, a non-invasive procedure or approach is used toablate sympathetic nerve fibers in the hepatic plexus and/or other nervefibers. In some embodiments, any of the modalities described herein,including, but not limited, to ultrasonic energy, HIFU energy,electrical energy, magnetic energy, light/radiation energy or any othermodality that can effect non-invasive ablation of nerve fibers, are usedin conjunction with a non-invasive (e.g., transcutaneous) procedure toablate sympathetic nerve fibers in the hepatic plexus and/or other nervefibers.

V. Stimulation

According to some embodiments, neuromodulation is accomplished bystimulating nerves and/or increasing neurotransmission. Stimulation, inone embodiment, may result in nerve blocking. In other embodiments,stimulation enhances nerve activity (e.g., conduction of signals).

In accordance with some embodiments, therapeutic modulation of nervefibers is carried out by neurostimulation of autonomic (e.g.,sympathetic or parasympathetic) nerve fibers. Neurostimulation can beprovided by any of the devices or systems described above (e.g.,ablation catheter or delivery catheter systems) and using any of theapproaches described above (e.g., intravascular, laparoscopic,percutaneous, non-invasive, open surgical). In some embodiments,neurostimulation is provided using a temporary catheter or probe. Inother embodiments, neurostimulation is provided using an implantabledevice. For example, an electrical neurostimulator can be implanted tostimulate parasympathetic nerve fibers that innervate the liver, whichcould advantageously result in a reduction in blood glucose levels bycounteracting the effects of the sympathetic nerves.

In some embodiments, the implantable neurostimulator includes animplantable pulse generator. In some embodiments, the implantable pulsegenerator comprises an internal power source. For example, the internalpower source may include one or more batteries. In one embodiment, theinternal power source is placed in a subcutaneous location separate fromthe implantable pulse generator (e.g., for easy access for batteryreplacement). In other embodiments, the implantable pulse generatorcomprises an external power source. For example, the implantable pulsegenerator may be powered via an RF link. In other embodiments, theimplantable pulse generator is powered via a direct electrical link. Anyother internal or external power source may be used to power theimplantable pulse generator in accordance with the embodiments disclosedherein.

In some embodiments, the implantable pulse generator is electricallyconnected to one or more wires or leads. The one or more wires or leadsmay be electrically connected to one or more electrodes. In someembodiments, one or more electrodes are bipolar. In other embodiments,one or more electrodes are monopolar. In some embodiments, there is atleast one bipolar electrode pair and at least one monopolar electrode.In some embodiments, one or more electrodes are nerve cuff electrodes.In other embodiments, one or more electrodes are conductive anchors.

In some embodiments, one or more electrodes are placed on or nearparasympathetic nerve fibers that innervate the liver. In someembodiments, the implantable pulse generator delivers an electricalsignal to one or more electrodes. In some embodiments, the implantablepulse generator delivers an electrical signal to one or more electrodesthat generates a sufficient electric field to stimulate parasympatheticnerve fibers that innervate the liver. For example, the electric fieldgenerated may stimulate parasympathetic nerve fibers that innervate theliver by altering the membrane potential of those nerve fibers in orderto generate an action potential.

In some embodiments, the implantable pulse generator recruits anincreased number of parasympathetic nerve fibers that innervate theliver by varying the electrical signal delivered to the electrodes. Forexample, the implantable pulse generator may deliver a pulse of varyingduration. In some embodiments, the implantable pulse generator variesthe amplitude of the pulse. In other embodiments, the implantable pulsegenerator delivers a plurality of pulses. For example, the implantablepulse generator may deliver a sequence of pulses. In some embodiments,the implantable pulse generator varies the frequency of pulses. In otherembodiments, the implantable pulse generator varies any one or moreparameters of a pulse including, but not limited to, duration,amplitude, frequency, and total number of pulses.

In some embodiments, an implantable neurostimulator chemicallystimulates parasympathetic nerve fibers that innervate the liver. Forexample, the chemical neurostimulator may be an implantable pump. Insome embodiments, the implantable pump delivers chemicals from animplanted reservoir. For example, the implantable pump may deliverchemicals, drugs, or therapeutic agents to stimulate parasympatheticnerve fibers that innervate the liver.

In some embodiments, the implantable neurostimulator uses anycombination of electrical stimulation, chemical stimulation, or anyother method to stimulate parasympathetic nerve fibers that innervatethe liver.

In some embodiments, non-invasive neurostimulation is used to stimulateparasympathetic nerve fibers that innervate the liver. For example,transcutaneous electrical stimulation may be used to stimulateparasympathetic nerve fibers that innervate the liver. In otherembodiments, any method of non-invasive neurostimulation is used tostimulate parasympathetic nerve fibers that innervate the liver.

In accordance with the embodiments disclosed herein, parasympatheticnerve fibers other than those that innervate the liver are stimulated totreat diabetes and/or other conditions, diseases, disorders, or symptomsrelated to metabolic conditions. For example, parasympathetic nervefibers that innervate the pancreas, parasympathetic nerve fibers thatinnervate the adrenal glands, parasympathetic nerve fibers thatinnervate the small intestine, parasympathetic nerves that innervate thestomach, parasympathetic nerve fibers that innervate the kidneys (e.g.,the renal plexus) or any combination of parasympathetic nerve fibersthereof may be stimulated in accordance with the embodiments hereindisclosed. Any autonomic nerve fibers can be therapeutically modulated(e.g., disrupted or stimulated) using the devices, systems, and methodsdescribed herein to treat any of the conditions, diseases, disorders, orsymptoms described herein (e.g., diabetes or diabetes-relatedconditions). In some embodiments, visceral fat tissue of the liver orother surrounding organs is stimulated. In some embodiments,intrahepatic stimulation or stimulation to the outer surface of theliver is provided. In some embodiments, stimulation (e.g., electricalstimulation) is not provided to the outer surface of the liver or withinthe liver (e.g., to the liver parenchyma), is not provided to the vagalor vagus nerves, is not provided to the hepatic portal vein, and/or isnot provided to the bile ducts.

Stimulation may be performed endovascularly or extravascularly. In oneembodiment, a stimulation lead is positioned intravascularly in thehepatic arterial tree adjacent parasympathetic nerves. The main hepaticbranch of the parasympathetic nerves may be stimulated by targeting alocation in proximity to the proper hepatic artery or multiple hepaticbranches tracking the left and right hepatic artery branches andsubdivisions. In one embodiment, the stimulation lead is positionedwithin a portion of the hepatoesophageal artery and activated tostimulate parasympathetic nerves surrounding the hepatoesophagealartery, as both vagal branches travel along the hepatoesophageal artery.

In one embodiment, the stimulation lead is positioned in the portal veinand activated to stimulate nerve fibers surrounding the portal vein,which may have afferent parasympathetic properties. In one embodiment,the stimulation lead is positioned across the hepatic parenchyma from acentral venous approach (e.g., via a TIPS-like procedure) or positionedby arterial access through the hepatic artery and then into the portalvein. In one embodiment, the portal vein is accessed extravascularlythrough a percutaneous approach. The stimulation lead may belongitudinally placed in the portal vein or wrapped around the portalvein like a cuff. Extravascular stimulation of the portal vein may beperformed by placing the stimulation lead directly on theparasympathetic fibers adhered to or within the exterior vessel wall. Invarious embodiments, the stimulation lead is placed percutaneously underfluoroscopy guidance, using a TIPS-like approach through the wall of theportal vein, by crossing the arterial wall, or by accessing the biliarytree.

In some embodiments, the stimulation lead is stimulated continuously orchronically to influence resting hepatic glucose product and glucoseuptake. In various embodiments, stimulation is performed when thesubject is in a fasting or a fed state, depending on a subject's glucoseexcursion profile. In some embodiments, stimulation may be programmed tooccur automatically at different times (e.g., periodically or based onfeedback). For example, a sensory lead may be positioned in the stomachor other location to detect food ingestion and trigger stimulation upondetection. In some embodiments, the stimulation is controlled orprogrammed by the subject or remotely by a clinician over a network.

In some embodiments, stimulation with 0.1 s-on, 4.9 s-off, 14 Hz, 0.3ms, 4 mA pulsed RF energy is used for sympathetic nerve stimulation andstimulation with 2 s-on, 3 s-off, 40 Hz, 0.3 ms, 4 mA pulsed RF energyis used for parasympathetic activation. However, other parameters of RFenergy or other energy types may be used.

Parasympathetic stimulation may also cause afferent effects along thevagus nerve, in addition to efferent effects to the liver resulting inchanges in hepatic glucose production and uptake. The afferent effectsmay cause other efferent neurally mediated changes in metabolic state,including, but not limited to one or more of the following: animprovement of beta cell function in the pancreas, increased muscleglucose uptake, changes in gastric or duodenal motility, changes insecretion or important gastric and duodenal hormones (e.g., an increasein ghrelin in the stomach to signal satiety, and/or an increase inglucagon-like peptide-1 (GLP-1) from the duodenum to increase insulinsensitivity).

VI. Examples

Examples provided below are intended to be non-limiting embodiments ofthe invention.

A. Example 1

Three dogs were put on a high fat, high fructose diet for four weeks,thereby rendering the dogs insulin resistant. As a control, a 0.9 g/kgoral gavage polycose dose was administered at four weeks afterinitiation of the high-fat, high fructose diet after an overnight fastand oral glucose tolerance tests were performed at various timeintervals to track glucose levels. The common hepatic arteries of thethree dogs were then surgically denervated. Another 0.9 g/kg oral gavepolycose dose was administered after an overnight fast about two tothree weeks following hepatic denervation. Oral glucose tolerance testswere performed at various time intervals after administration of thepolycose. FIG. 23A illustrates a graph of the average venous plasmaglucose over time for the three dogs reported by the two oral glucosetolerance tests (OGTTs). The curve with the data points represented byblack circles represents the average of the glucose measurements fromthe OGTT testing of the three dogs after the four weeks of high fat,high fructose diet before hepatic denervation. The oral gavage polycosedoses were administered at time zero shown in FIG. 23A. The curve withthe data points represented as white circles represents the average ofthe glucose measurements from the OGTT testing of the same three dogstwo to three weeks after hepatic denervation. As can be seen in FIG.23A, the glucose values after hepatic denervation peaked at lowerglucose concentrations and dropped much more rapidly than the glucosevalues prior to hepatic denervation. In accordance with severalembodiments, the results of the study provide strong evidence of theefficacy of hepatic denervation for controlling blood glucose levels.

B. Example 2

FIG. 23B illustrates the net hepatic glucose balanced obtained during ahyperglycemic-hyperinsulinemic clamp study. The data represented withcircle indicators (HDN) represents the average net hepatic glucoselevels of the same 3 dogs from Example 1 four weeks after denervation.The data represented with square indicators (HF/HF) represents theaverage net hepatic glucose levels of 5 dogs that were fed a high fat,high fructose diet. The data represented with the triangle indicators(Chow) represents the average net hepatic glucose levels of 5 dogs fed anormal diet. The data shows that toward the end of the curves, hepaticdenervation restores net hepatic glucose balance to about 60% back tobaseline, which suggests insulin resistance in the liver in the HF/HFdog model is largely corrected by hepatic denervation, and whichindicates that hepatic denervation has an effect on hepatic glucoseuptake and/or hepatic glucose production.

C. Example 3

A hepatic artery was harvested from a porcine liver as far proximal asthe common hepatic artery and as far distal as the bifurcation of theleft hepatic artery and the right hepatic artery. The arterial plexuswas sandwiched between two sections of liver parenchyma (a “bed” and a“roof”), and placed in a stainless steel tray to serve as a returnelectrode. A total of 3 arteries were ablated using a RADIONICS RFG-3CRF generator using a NiTi/dilator sheath, having an exposed surface ofapproximately 1/16″ to 3/32″ in length. RF energy was applied for 117seconds in each case, with the generator power setting at 4 (generallydelivering 2-3 W into 55-270Ω). For the first 2 sample arteries, aK-type thermocouple was used to monitor extravascular temperatures,which reached 50-63° C. The first ablation was performed in the lefthepatic artery, the second ablation was performed in the right hepaticartery, and the third ablation was performed in the proper hepaticartery. For the first ablation in the left hepatic artery having a lumendiameter of 1.15 mm, two ablation zone measurements were obtained (0.57mm and 0.14 mm). A roughly 3 mm coagulation zone was measured. Theelectrode exposure distance was 3/32″. For the second ablation in theright hepatic artery, an electrode exposure distance of 1/16″ was used.The generator impeded out due to high current density and no ablationlesion was observed. For the third ablation of the proper hepatic arteryhaving a lumen diameter of 2 mm and using an electrode exposure distancewas 3/32″, three ablation zone widths of 0.52 mm, 0.38 mm and 0.43 mmwere measured. The measured ablation zone widths support the fact thatnerves surrounding the proper hepatic artery (which may be tightlyadhered to or within the arterial wall) can be denervated using anintravascular approach. Histological measurements of porcine hepaticartery segments have indicated that hepatic artery nerves are within1-10 medial thicknesses (approximately 1-3 mm) from the lumen surface,thereby providing support for modulation (e.g., denervation, ablation,blocking conduction of, or disruption) of nerves innervating branches ofthe hepatic artery endovascularly using low-power RF energy (e.g., lessthan 10 W and/or less than 1 kJ) or other energy modalities. Nervesinnervating the renal artery are generally within the 4-6 mm range fromthe lumen of the renal artery.

D. Example 4

An acute animal lab was performed on a common hepatic artery and aproper hepatic artery of a porcine model. The common hepatic artery wasablated 7 times and the proper hepatic artery was ablated 3 times.According to one embodiment of the invention, temperature-controlalgorithms (e.g., adjusting power manually to achieve a desiredtemperature) were implemented at temperatures ranging from 50° C. to 80°C. and for total ablation times ranging from 2 to 4 minutes. Accordingto one embodiment of the invention, the electrode exposure distance forall of the ablations was 3/32″. Across all ablations the ablationparameters generally ranges as follows, according to various embodimentsof the invention: resistance ranged from about 0.1 ohms to about 869ohms (generally about 100 ohms to about 300 ohms), power output rangedfrom about 0.1 W to about 100 W (generally about 1 Watt to about 10Watts), generator voltage generally ranged from about 0.1 V to about 50V, current generally ranged from about 0.01 A to about 0.5 A, andelectrode tip temperature generally ranged from about 37° C. to about99° C. (generally +/−5° C. from the target temperature of eachablation). Energy was titrated on the basis of temperature and time upto approximately 1 kJ or more in many ablations. Notching was observedunder fluoroscopy in locations corresponding to completed ablations,which may be a positive indicator of ablative success, as the thermaldamage caused arterial spasm.

It was observed that, although separation of ablation regions by 1 cmwas attempted, the ablation catheter skipped distally during theablation procedure, which is believed to have occurred due to themovement of the diaphragm during the ablation procedure, thereby causingmovement of the anatomy and hepatic arterial vasculature surrounding theliver (which may be a unique challenge for the liver anatomy).

Unlike previous targets for endovascular ablation (e.g., renal arteries,which course generally straight toward the kidneys), the hepaticarterial vasculature is highly variable and tortuous. It was observedduring the study that catheters having a singular articulated shape maynot be able to provide adequate and consistent electrode contact forceto achieve ablative success. For example, in several ablation attemptsusing an existing commercially-available RF ablation catheter, withenergy delivered according to a manually-implementedconstant-temperature algorithm, the power level was relatively high withlow variability in voltage output required to maintain the targettemperature. This data is generally indicative of poor vessel wallcontact, as the electrode is exposed to higher levels of cooling fromthe blood (thereby requiring higher power output to maintain aparticular target temperature). Additionally, tissue resistivity is afunction of temperature. Although the tissue within the vessel wall isspatially fixed, there is constant mass flux of “refreshed” blood tissuein contact with the electrode at physiologic temperatures. Consequently,in one embodiment, when the electrode is substantially in contact with“refreshed” blood at physiologic temperatures, the electrode “sees”substantially constant impedance. Due to the correlation betweenimpedance and voltage (e.g., P=V²/R), the substantially constantimpedance is reflected in a substantially constant (less variable)voltage input required to maintain a target electrode tip temperature.Therefore, particular embodiments (such as those described, for example,in FIGS. 14 and 15 advantageously enable adequate electrode contact inany degree of hepatic artery tortuosity that may be encounteredclinically.

E. Example 5

A numerical model representing the hepatic artery and surroundingstructures was constructed in COMSOL Multiphysics 4.3. using anatomical,thermal, and electrical tissue properties. Thermal and electricalproperties are a function of temperature. Electrical conductivity(sigma, or σ) generally varies according to the equationσ=σ₀e^(0.015(T−T) ⁰ ⁾, where σ₀ is the electrical conductivity measuredat physiologic temperatures (T₀) and T is temperature. With reference toFIGS. 22A-22D, model geometry was assessed and included regionsrepresenting the hepatic artery lumen, bile duct 2205, and portal vein2210. The bile 2205 duct and portal vein 2210 were modeled as groundedstructures, highlighting the effect of these structures on current flow.By calculating liver blood flow and the relative contributions from thehepatic artery and portal vein 2210, we determined the flow in thehepatic artery was significantly lower than flow rates in other arteries(e.g., renal arteries). In one embodiment, the estimated flow rate was139.5 mL/min. for the hepatic artery. Using the model described above,independent solutions were first obtained for monopolar and bipolarelectrode configuration. A geometric model corresponding to the commonhepatic artery was created and a time-dependent solution was calculatedin COMSOL using the bioheat equation,

${{\rho_{b}c_{pb}\frac{\partial T}{\partial t}} = {{\nabla\left( {k{\nabla T_{t}}} \right)} + {\rho_{b}{{uc}_{pb}\left( {T_{B} - T} \right)}} + q_{m}}},$which, in one embodiment, relates the temperature at any point in themodel as a function of the temperature gradient in the tissue, bloodperfusion, blood temperature entering the geometric region of interest,and the heat generated (q_(m)) as a function of RF energy deposition.

FIGS. 22A and 22B illustrate a geometric model of RF energy depositionin the common hepatic artery using a single electrode, with theconductivity of the bile duct 2205 and the portal vein 2210 grounded(FIG. 22A) and accounted for (FIG. 22B). As shown in FIG. 22B, biliaryand portal vein conductivity can influence where ablation energy travelswhen a single electrode 2215 is used. FIGS. 22C and 22D illustrate ageometric model of RF energy deposition in the common hepatic artery fora bipolar electrode configuration 2215, with the conductivity of thebile duct 2205 and the portal vein 2210 grounded (FIG. 22C) andaccounted for (FIG. 22D).

The shape of the electric field and resulting thermal ablation 2220 wassignificantly affected in the monopolar ablation model due to biliaryand portal vein conductivity (as shown in FIGS. 22A and 22B). Minimaleffects due to biliary and portal vein conductivity (e.g., shapingeffects) were observed in the shape of the electric field and resultingthermal ablation 2220 for the bipolar ablation model (shown in FIGS. 22Cand 22D). FIGS. 22A and 22B were obtained when the pair of bipolarelectrodes were modeled, according to one embodiment, as disposed at alocation that is substantially tangent to the inner lumen of the artery,with each individual electrode having an arc length of 20 degrees andwith an inter-electrode spacing of 10 degrees. In one embodiment, theedges of the electrodes have radii sufficient to reduce currentconcentrations (less than 0.001″). In several embodiments, the bipolarconfiguration advantageously provides effective ablation (e.g., thermalablation of the hepatic artery) without significant effect on shaping ofthe ablation zone, despite the effects of biliary and portal veinconductivity due to proximity of the bile duct and portal vein to thecommon hepatic artery.

F. Example 6

Independent modeling solutions were obtained for an ablation withconvective cooling (e.g., provided by blood flow alone) and for anablation incorporating active cooling (e.g., 7° C. coolant) using thesame bipolar configuration model described above in Example 5. Themodels showed significantly decreased temperatures at the locationcorresponding to the lumen (endothelial) interface. Higher power (45%higher power) was delivered to the active cooling model. Even withhigher power delivered (e.g., 45% higher power) to the active coolingmodel, the endothelial region of the common hepatic artery remained cool(e.g. less than hyperthermic temperatures up to 1 mm from the lumen).The effective shaping of the thermal ablation zone was also directedinto a more linear shape directed radially in the active cooling model.It was observed, that, in accordance with several embodiments, ascooling power is increased and RF power is increased, the linear shapingeffect was magnified, thereby rendering the ablation zone capable ofbeing directed or “programmed” (e.g., toward a more targeted location).

In some embodiments, the neuromodulation catheter (e.g., ablationcatheter) designs described herein (e.g., the balloon catheters of FIGS.13A-13C) advantageously provide effective modulation of nervesinnervating branches of the hepatic artery without causing, or at leastminimizing endothelial damage, if desired. For example, the cathetersdescribed herein can occlude the hepatic artery (e.g., using a balloon)and then circulate coolant in the region of the ablation (e.g., withinthe lumen of the balloon). In some embodiments, the catheters providethe unique advantage of both higher power net energy offered throughlarger electrode surface area (which may be enabled by the largerelectrode sizes that can be manufactured on a balloon) and increaseddeposition time (which may be permitted by the ability to occlude flowto the hepatic artery for longer periods of time). In accordance withseveral embodiments, the increase in energy density through higher powermitigates the risk of damage to the endothelial wall by the flow ofcoolant within the balloon.

While the devices, systems and methods described herein have primarilyaddressed the treatment of diabetes (e.g., diabetes mellitus), otherconditions, diseases, disorders, or syndromes can be treated using thedevices, systems and methods described herein, including but not limitedto ventricular tachycardia, atrial fibrillation or atrial flutter,inflammatory diseases, endocrine diseases, hepatitis, pancreatitis,gastric ulcers, gastric motility disorders, irritable bowel syndrome,autoimmune disorders (such as Crohn's disease), obesity, Tay-Sachsdisease, Wilson's disease, NASH, NAFLD, leukodystrophy, polycystic ovarysyndrome, gestational diabetes, diabetes insipidus, thyroid disease, andother metabolic disorders, diseases, or conditions.

Although several embodiments and examples are disclosed herein, thepresent application extends beyond the specifically disclosedembodiments to other alternative embodiments and/or uses of theinventions and modifications and equivalents thereof. It is alsocontemplated that various combinations or subcombinations of thespecific features and aspects of the embodiments may be made and stillfall within the scope of the inventions. Accordingly, it should beunderstood that various features and aspects of the disclosedembodiments can be combine with or substituted for one another in orderto form varying modes of the disclosed inventions. Thus, it is intendedthat the scope of the present inventions herein disclosed should not belimited by the particular disclosed embodiments described above.

What is claimed is:
 1. A method of treating non-alcoholic fatty liverdisease, comprising: positioning a distal portion of an energy deliverydevice within a common hepatic artery of a subject; at least partiallyblocking one or more sympathetic nerves that innervate a liver using theenergy delivery device by intravascularly delivering energy through awall of the common hepatic artery at a target location sufficient totreat non-alcoholic fatty liver disease; and removing the energydelivery device from the subject, wherein the energy delivery device isconfigured to contact the wall of a portion of the common hepatic arteryat the target location while the energy is being delivered.
 2. Themethod of claim 1, wherein the energy delivery device comprises one ormore electrodes, and wherein the energy delivered by the energy deliverydevice comprises radiofrequency (RF) energy delivered by the one or moreelectrodes.
 3. The method of claim 1, wherein the energy delivery devicecomprises one or more ultrasound transducers.
 4. The method of claim 1,further comprising at least partially occluding the portion of thecommon hepatic artery.
 5. The method of claim 4, wherein at leastpartially occluding the portion of the hepatic artery comprises fullyoccluding the portion of the common hepatic artery.
 6. The method ofclaim 1, wherein the energy delivery device comprises a balloon catheterconfigured to at least partially occlude the portion of the commonhepatic artery.
 7. The method of claim 6, wherein the balloon cathetercomprises one or more electrodes configured to contact the wall of thecommon hepatic artery upon expansion of at least one balloon of theballoon catheter.
 8. The method of claim 1, wherein the energy deliverydevice comprises a catheter with a flexible distal end configured tonavigate arterial anatomy having a bend radius of 5 mm.
 9. The method ofclaim 2, wherein the RF energy is delivered at a frequency in the rangeof 50 kHz to 5 MHz; and wherein the RF energy is delivered to heat theone or more sympathetic nerves to a temperature of up to 90 degreesCelsius and sufficient to cause ablation of the one or more sympatheticnerves.
 10. The method of claim 3, wherein the energy is delivered at afrequency in the range of 20 kHz to 20 MHz.
 11. The method of claim 1,further comprising providing cooling to a portion of a tissue that isnot being targeted by the energy.
 12. A method of treating non-alcoholicfatty liver disease, comprising: positioning a distal end of aneuromodulation device within a hepatic artery segment of a subject;modulating one or more nerves that innervate a liver using theneuromodulation device sufficient to treat non-alcoholic fatty liverdisease; and removing the neuromodulation device from the subject,wherein at least a portion of the distal end of the neuromodulationdevice is configured to contact a wall of the hepatic artery segment ata target location while the one or more nerves are being modulated. 13.The method of claim 12, wherein the neuromodulation device is deliveredintravascularly through a femoral or radial artery to the targetlocation within the hepatic artery segment.
 14. The method of claim 12,wherein the neuromodulation device comprises an radiofrequency (RF)energy delivery catheter comprising one or more electrodes at a distalsection of the RF energy delivery catheter configured to contact thewall of the hepatic artery segment while the one or more nerves arebeing modulated.
 15. The method of claim 12, wherein modulating the oneor more nerves comprises denervating one or more sympathetic nerves of ahepatic plexus.
 16. The method of claim 12, further comprising at leastpartially occluding the hepatic artery segment.
 17. The method of claim12, wherein a contact pressure between 0.1 g/mm² and 100 g/mm² isexerted on the wall.
 18. A method of treating non-alcoholic fatty liverdisease, comprising: providing an energy delivery catheter configuredfor: accessing a portion of vasculature in the vicinity of a hepaticplexus of a subject; and delivering energy through a wall of thevasculature sufficient to modulate one or more nerves of the hepaticplexus, wherein modulation of the one or more nerves effects treatmentof non-alcoholic fatty liver disease.
 19. The method of claim 18,wherein the energy comprises radiofrequency (RF) energy delivered to theone or more nerves at a frequency in the range of 50 kHz to 5 MHz, andwherein the RF energy is delivered to heat the one or more nerves to atemperature of up to 90 degrees Celsius and sufficient to cause ablationof the one or more nerves.
 20. The method of claim 18, wherein at leasta portion of a distal end of the energy delivery catheter is configuredto contact the wall of a hepatic artery segment within the vasculatureat a target location while the one or more nerves are being modulated.